Sublingual films

ABSTRACT

The invention features sublingual film formulations of dopamine agonists and methods of treating Parkinson&#39;s disease, tremors, restless leg syndrome, sexual dysfunction, and depressive disorders therewith.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/858,638, filed Apr. 8, 2013, which is a continuation of U.S. patentapplication Ser. No. 13/445,656, filed Apr. 12, 2012, now U.S. Pat. No.8,414,922, which is a continuation of International Patent ApplicationNo. PCT/US2011/065665, filed Dec. 16, 2011, which claims the benefit ofU.S. Provisional Application No. 61/483,864, filed May 9, 2011, and U.S.Provisional Application No. 61/423,858, filed Dec. 16, 2010. Each of theaforementioned disclosures are incorporated herein by reference in theirentirety.

STATEMENT UNDER 35 U.S.C. §103(C)(2)(C)

The claimed invention was made as a result of activities undertakenwithin the scope of a joint research agreement between CynapsusTherapeutics, Inc. and ARx, LLC.

BACKGROUND OF THE INVENTION

The invention relates to compositions including a dopamine agonistformulated for sublingual administration and the use of suchcompositions for the treatment of Parkinson's disease.

Parkinson's disease (PD) is a progressive degenerative disease of thecentral nervous system. The risk of developing Parkinson's diseaseincreases with age, and afflicted individuals are usually adults over40. Parkinson's disease occurs in all parts of the world, and affectsmore than 1.5 million individuals in the United States alone.

While the primary cause of Parkinson's disease is not known, it ischaracterized by degeneration of dopaminergic neurons of the substantianigra. The substantia nigra is a portion of the lower brain, or brainstem that helps control voluntary movements. The shortage of dopamine inthe brain caused by the loss of these neurons is believed to cause theobservable disease symptoms.

The symptoms of PD vary from patient to patient. The most common symptomis a paucity of movement and rigidity, characterized by an increasedstiffness of voluntary skeletal muscles. Additional symptoms includeresting tremor, bradykinesia (slowness of movement), poor balance, andwalking problems. Common secondary symptoms include depression, sleepdisturbance, dizziness, stooped posture, dementia, problems with speech,breathing, and swallowing. The symptoms become progressively worse withtime and ultimately result in death.

A variety of therapeutic treatments for PD are available. Perhaps thebest known is levodopa, a dopamine precursor. While levodopaadministration can result in a dramatic improvement in symptoms,patients can experience serious side-effects, including nausea andvomiting. Concurrent carbidopa administration with levodopa is asignificant improvement, with the addition of carbidopa inhibitinglevodopa metabolism in the gut, liver and other tissues, therebyallowing more levodopa to reach the brain. Other dopamine agonists, suchas bromocriptine, pergolide, pramipexole, and andropinirole are alsoused to treat Parkinson's disease, and can be administered to PDpatients either alone or in combination with levodopa.

Many patients develop involuntary choreiform movements which are theresult of excessive activation of dopamine receptors. These movementsusually affect the face and limbs and can become very severe. Suchmovements disappear if the dose of dopamine precursor (e.g., levodopa)or dopamine agonist is reduced, but this typically causes rigidity toreturn. Moreover, the margin between the beneficial and the unwantedeffects appear to become progressively narrower as the period ofchemotherapeutic treatment lengthens.

A further complication of long-term chemotherapeutic treatment withdopamine agonists is the development of rapid fluctuations in clinicalstate where the patient switches suddenly between mobility andimmobility for periods ranging from a few minutes to a few hours. Thefluctuations are of several general types. “Wearing-off” phenomena aredeteriorations in the relief afforded by a dose of levodopa before thenext dose takes effect (Van Laar T., CNS Drugs, 17:475 (2003)). Becausethey are related to a patient's dose schedule, such periods are oftenrelatively predictable (Dewey R B Jr., Neurology, 62(suppl 4):S3-S7(2004)). In contrast, “on-off” phenomena are sudden transitions from an“on” period of levodopa benefit to an “off” period of akinesia,rigidity, and tremor that occur in minutes or even seconds, (Swope D M.,Neurology, 62(suppl 4):S27-S31 (2004)) with no discernible relation to apatient's dose schedule. Two other phenomena are the delayed “on”effect, in which levodopa's effects are substantially delayed, and dosefailure (also known as the no-“on” or skipped-dose effect), in which noeffects occur at all. These various “off” states can produce such anabrupt loss of mobility that the patient may suddenly stop while walkingor be unable to rise from a chair in which he had sat down normally afew moments earlier.

Subcutaneous injections of apomorphine have proved to be effective inthe treatment of “on-off” fluctuations in Parkinson's disease within 5to 15 minutes, and last for 45 to 90 minutes. Trials have shownconsistent reversal of “off” period akinesia, a decrease in dailylevodopa requirements and consequently a decrease in the amount of “on”period dyskinesias. Advantages over other dopamine agonists include aquick onset of action and lower incidence of psychologicalcomplications. For a “rescue therapy” in patients with “on-off”fluctuations, apomorphine also has the advantage over other dopamineagonists that it has a relatively short half-life.

Numerous formulations and routes of administration for apomorphine havebeen studied and apomorphine therapy has been found to be hampered byvarious complications. For example, oral administration of apomorphinetablets has required high doses to achieve the necessary therapeuticeffect because apomorphine administered by this route undergoesextensive metabolism in the small intestine and/or, upon absorption, inthe liver; sublingual administration of apomorphine tablets causedsevere stomatitis on prolonged use with buccal mucosal ulceration inhalf the patients treated (see Deffond et al., J. Neurol. Neurosurg.Psychiatry 56:101 (1993)); and intranasal administration producedtransient nasal blockage, burning sensation and swollen nose and lips(see Koller et al., Neurology 62:S22 (2004)). While subcutaneousinjections of apomorphine have proven effective, an injection by needleis difficult for Parkinson's patients because of impaired motorfunction. Furthermore, a common side effect of subcutaneous injection isthe development of nodules, which often become infected, necessitatingantiobiotic treatment or surgical debridement (see Prietz et al., J.Neurol. Neurosurg. Psychiatry 65:709 (1998)).

There is a need for new formulations of dopamine agonists which aresafe, effective, and easy for a Parkinson's patient to use.

SUMMARY OF THE INVENTION

The invention features sublingual formulations including a dopamineagonist, or a salt thereof. The formulations can be useful for thetreatment of Parkinson's disease, tremors, restless leg syndrome, sexualdysfunction, and depressive disorders therewith.

In one aspect, the invention features a pharmaceutical composition inunit dosage form formulated for sublingual administration, wherein theunit dosage form is a film including one or more disintegrants (e.g.,materials that favor disintegration or fast dissolution by virtue oftheir solubility in water, such as hydrolyzed starches, sugars, andglycerin, which may play a dual role as a plasticizer and disintegrant)and a plasticizing agent, the film having a first portion includingapomorphine hydrochloride, and a second portion including pHneutralizing agent, wherein the unit dosage form includes from 0.5 to 5mg, from 4 to 10 mg, or from 8 to 20 mg of apomorphine hydrochloride andthe pH neutralizing agent is present in an amount sufficient to producea solution having a pH of between 3.0 and 6.0, preferably between 4.5and 6.5, (e.g., a pH of between 2.5 and 4.5, 3.0 and 6.0, 3.5 and 6.5,4.5 and 6.5, or 5.0 and 6.0) when the unit dosage form is placed inunbuffered water at pH 7 (e.g., the pH observed within 5 minutes ofplacing the unit dosage form in 1, 5, or 10 mL of unbuffered water). Thefilm can include from 1 to 50% (w/w) (e.g., 1±0.75%, 2±1.5%, 3±0.5%,5±2%, 7.5±2.5%, 10±2%, 14±3%, 18±4%, 22±5%, 25±5%, 30±5%, 35±5%, 40±5%,45±5%, or 50±5% (w/w)) of the one or more disintegrants. In certainembodiments, the unit dosage form further includes a high molecularweight polymer having a weight average molecular weight of greater than60 KDa selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methylcellulose. In other embodiments, the unit dosage form further includes alow molecular weight polymer having a weight average molecular weight offrom 5 KDa to 50 KDa selected from hydroxypropyl cellulose,hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose, and methyl cellulose. The pH neutralizing agent can be anorganic base (e.g., pyridoxine, meglumine, or any organic base describedherein) or an inorganic base (e.g., magnesium hydroxide, sodiumbicarbonate, or an inorganic base described herein). In particularembodiments, the unit dosage form includes 35±5% (w/w) disintegrant,from 0.5 to 5 mg, from 4 to 10 mg, or from 8 to 20 mg of apomorphinehydrochloride and pyridoxine present in an amount sufficient to producea solution having a pH of between 4.5 and 6.5 when the unit dosage formis placed in unbuffered water at pH 7.

In a related aspect, the invention features a pharmaceutical compositionin unit dosage form formulated for sublingual administration, whereinthe unit dosage form is a film including: (i) apomorphine hydrochloride;(ii) a low molecular weight polymer having a weight average molecularweight of from 5 KDa to 50 KDa selected from hydroxypropyl cellulose,hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose, and methyl cellulose; and (iii) a high molecular weightpolymer having a weight average molecular weight of greater than 60 KDaselected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose,hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose,wherein the unit dosage form includes from 0.5 to 5 mg, from 4 to 10 mg,or from 8 to 20 mg of apomorphine hydrochloride.

The invention further features a pharmaceutical composition in unitdosage form formulated for sublingual administration, wherein the unitdosage form is a bilayer film having a first layer and a second layer,the second layer including a pH neutralizing agent and the first layerincluding: (i) apomorphine hydrochloride; (ii) a low molecular weightpolymer having a weight average molecular weight of from 5 KDa to 50 KDaselected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose,hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose;and (iii) a high molecular weight polymer having a weight averagemolecular weight of greater than 60 KDa selected from hydroxypropylcellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose,carboxymethyl cellulose, and methyl cellulose, wherein the unit dosageform includes from 0.5 to 5 mg, from 4 to 10 mg, or from 8 to 20 mg ofapomorphine hydrochloride and the pH neutralizing agent is present in anamount sufficient to produce a solution having a pH of between 3.0 and6.0, preferably between 4.5 and 6.5, (e.g., a pH of between 2.5 and 4.5,3.0 and 6.0, 3.5 and 6.5, 4.5 and 6.5, or 5.0 and 6.0) when the unitdosage form is placed in unbuffered water at pH 7 (e.g., the pH observedwithin 5 minutes of placing the unit dosage form in 1, 5, or 10 mL ofunbuffered water). The pH neutralizing agent can be an organic base(e.g., pyridoxine, meglumine, or any organic base described herein) oran inorganic base (e.g., magnesium hydroxide, sodium bicarbonate, or aninorganic base described herein). In particular embodiments, the unitdosage form includes an antioxidant, 1±0.5% (w/w) glycerol monosterate,35±5% (w/w) disintegrant, from 0.5 to 5 mg, from 4 to 10 mg, or from 8to 20 mg of apomorphine hydrochloride and pyridoxine present in anamount sufficient to produce a solution having a pH of between 4.5 and6.5 when the unit dosage form is placed in unbuffered water at pH 7.

In one embodiment of any of the above unit dosage forms, the unit dosageform can include from 0.2 to 5% (w/w) e.g., 0.5±0.25%, 0.75±0.25%,1±0.5%, 1.5±0.5%, 2±0.5%, 2.5±0.5%, 3±0.5%, 3.5±0.5%, 4±0.5%, or 5±0.5%(w/w)) of a permeation enhancer (e.g., an ionic surfactant, nonionicsurfactant, polysorbate, derivatives of tocopherol, poloxamer,monoglyceride, diglyceride, fatty acid, fatty alcohol, mixtures thereof,or any permeation enhancer described herein). In particular embodiments,the permeation enhancer is glycerol monosterate. In another embodimentof any of the above unit dosage forms, the unit dosage form can includean antioxidant (e.g., from 0.05 to 2.5% (w/w) (e.g., 0.05±0.025%,0.1±0.075%, 0.3±0.1%, 0.5±0.25%, 0.75±0.25%, 1±0.5%, 1.5±0.5%, 2±0.5%,or 2.5±0.5% (w/w)) metabisulfite, or any antioxidant described herein.In certain embodiments of the above unit dosage forms, the unit dosageform can further include from 3 to 18% (w/w) (e.g., 3 to 12%, 3±1%,5±2%, 7.5±2.5%, 10±3%, 12±3%, 15±3%, or 18±3% (w/w)) plasticizing agent,such as a polyol (e.g., sorbitol, mannitol, maltitol, xylitol, glycerol,propylene glycol, or polyethylene glycol), oleic acid, or triacetin. Inparticular embodiments of the above unit dosage forms, the unit dosageform can include from 1 to 50% (w/w) (e.g., 1±0.75%, 2±1.5%, 3±0.5%,5±2%, 7.5±2.5%, 10±2%, 14±3%, 18±4%, 22±5%, 25±5%, 30±5%, 35±5%, 40±5%,45±5%, or 50±5% (w/w)) hydrolyzed starch. The hydrolyzed starch can be adextrin, a maltodextrin, or any hydrolyzed starch described herein. Instill another embodiment of any of the unit dosage forms of theinvention, the unit dosage form can have a sublingual bioavailability ofgreater than 40% (e.g., a sublingual bioavailability of from 40 to 70%,45 to 85%, 55 to 95%, 65 to 100%, 70 to 100%, 70 to 99%, 75 to 100%, 75to 99%, or 80 to 99%). In particular embodiments, any of the unit dosageforms described herein can have a T_(max) of from 10 to 25 minutes(e.g., 9±3, 10±3, 11±3, 12±3, 13±3, 14±3, 15±3, 16±3, 17±3, 18±3, 20±3,22±3, 24±3, or 25±3 minutes). In still another embodiment of any of theabove unit dosage forms, the unit dosage form, following sublingualadministration to a subject, produces an average circulating apomorphineconcentration of at least 3 ng/mL within a period of from 5 to 15minutes following the administration. For example, the unit dosage formcan produce an average circulating concentration of from 3 to 6 ng/mLwithin 7 to 10 minutes, from 5 to 10 ng/mL within 5 to 10 minutes, from7 to 12 ng/mL within 5 to 10 minutes, from 10 to 16 ng/mL within 5 to 10minutes, from 3 to 6 ng/mL within 7 to 15 minutes, from 5 to 10 ng/mLwithin 7 to 15 minutes, from 7 to 12 ng/mL within 7 to 15 minutes, from10 to 16 ng/mL within 7 to 15 minutes, from 3 to 6 ng/mL within 15 to 20minutes, from 5 to 10 ng/mL within 15 to 20 minutes, from 7 to 12 ng/mLwithin 15 to 20 minutes, or from 10 to 16 ng/mL within 15 to 20 minutesfollowing the administration. In one embodiment of any of the above unitdosage forms, the unit dosage form when administered sublingually to asubject is non-irritating (e.g., non-irritating using the test ofExample 7). In one particular embodiment of any of the above unit dosageforms, the unit dosage form is an individual film packaged in a sealedplastic-lined aluminum foil, wherein the unit dosage form is stable fora period of at least 2 months, 4 months, or 6 months at 40° C. (e.g.,uncolored using the test described in Example 8).

The invention features a pharmaceutical composition in unit dosage formformulated for sublingual administration, the unit dosage form having afirst portion including an acid addition salt of a dopamine agonist, anda second portion including a pH neutralizing agent, wherein the dopamineagonist is selected from bromocriptine, cabergoline,dihydroergocryptine, lisuride, piribedil, pergolide, pramipexole,rotigotine, ropinirol, and acid addition salts thereof. In particularembodiments, the unit dosage form is a lozenge, a pill, a tablet, afilm, or a strip.

The invention features a pharmaceutical composition in unit dosage formformulated for sublingual administration, wherein the unit dosage formis a film including: (i) from 10 to 75% (w/w) (e.g., 30 to 75%, 10±5%,15±5%, 20±5%, 25±5%, 30±5%, 35±5%, 40±5%, 45±5%, 50±5%, 55±5%, 60±5%,65±5%, 70±5%, or 75±5% (w/w)) dopamine agonist, or an acid addition saltthereof; (ii) from 0.5 to 16% (w/w) (e.g., 0.5 to 10%, 0.5±0.1%, 1±0.5%,2±0.75%, 3±1%, 5±1%, 6±2%, 7±3%, 8±3%, 9±3%, 12±3%, or 16±3% (w/w)) of alow molecular weight polymer having a weight average molecular weight offrom 5 KDa to 50 KDa (e.g., 5±3, 8±3, 10±3, 15±5, 18±5, 22±6, 28±6,34±8, 44±8, or 50±10 KDa) selected from hydroxypropyl cellulose,hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose, and methyl cellulose; and (iii) from 4 to 35% (w/w) (e.g., 4to 20%, 4±2%, 5±2.5%, 7.5±3%, 10±3.5%, 14±5%, 18±5%, 20±6%, 25±6%,30±6%, or 35±6% (w/w)) of a high molecular weight polymer having aweight average molecular weight of greater than 60 KDa (e.g., 60 KDa to500 KDa, 60 KDa to 1,000 KDa, 80 KDa to 120 KDa, 100 KDa to 300 KDa, 220KDa to 500 KDa, or 400 KDa to 800 KDa) selected from hydroxypropylcellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose,carboxymethyl cellulose, and methyl cellulose. In certain embodimentsthe film has a surface coated with a pH neutralizing agent (e.g., acoating or dusting of an inorganic or organic base). In still otherembodiments, the unit dosage form when placed in 1 mL of unbufferedwater at pH 7 results in a solution having a pH of between 2.5 and 6.5,preferably between 4.5 and 6.5, (e.g., a pH of between 2.5 and 4.5, 3.0and 6.0, 3.5 and 6.5, 4.5 and 6.5, or 5.0 and 6.0), and has a sublingualbioavailability of greater than 40% (e.g., a sublingual bioavailabilityof from 40 to 70%, 45 to 85%, 55 to 95%, 65 to 100%, 70 to 100%, 70 to99%, 75 to 100%, 75 to 99%, or 80 to 99%). In particular embodiments,the dopamine agonist is selected from apomorphine, an apomorphineprodrug, bromocriptine, cabergoline, dihydroergocryptine, lisuride,piribedil, pergolide, pramipexole, rotigotine, ropinirol, and acidaddition salts thereof.

In a related aspect, the invention features a pharmaceutical compositionin unit dosage form formulated for sublingual administration, whereinthe unit dosage form is a bilayer film having a first layer and a secondlayer, the first layer including: (i) from 10 to 75% (w/w) (e.g., 30 to75%, 10±5%, 15±5%, 20±5%, 25±5%, 30±5%, 35±5%, 40±5%, 45±5%, 50±5%,55±5%, 60±5%, 65±5%, 70±5%, or 75±5% (w/w)) dopamine agonist, or an acidaddition salt thereof; (ii) from 0.5 to 16% (w/w) (e.g., 0.5 to 10%,0.5±0.1%, 1±0.5%, 2±0.75%, 3±1%, 5±1%, 6±2%, 7±3%, 8±3%, 9±3%, 12±3%, or16±3% (w/w)) of a low molecular weight polymer having a weight averagemolecular weight of from 5 KDa to 50 KDa (e.g., 5±3, 8±3, 10±3, 15±5,18±5, 22±6, 28±6, 34±8, 44±8, or 50±10 KDa) selected from hydroxypropylcellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose,carboxymethyl cellulose, and methyl cellulose; and (iii) from 4 to 35%(w/w) (e.g., 4 to 20%, 4±2%, 5±2.5%, 7.5±3%, 10±3.5%, 14±5%, 18±5%,20±6%, 25±6%, 30±6%, or 35±6% (w/w)) of a high molecular weight polymerhaving a weight average molecular weight of greater than 60 KDa (e.g.,60 KDa to 500 KDa, 60 KDa to 1,000 KDa, 80 KDa to 120 KDa, 100 KDa to300 KDa, 220 KDa to 500 KDa, or 400 KDa to 800 KDa) selected fromhydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethylcellulose, carboxymethyl cellulose, and methyl cellulose, and whereinthe second layer includes a pH neutralizing agent and from 15 to 50%(w/w) (e.g., 15±5%, 20±5%, 25±5%, 30±5%, 35±5%, 40±5%, 45±5%, or 50±5%(w/w)) of a high molecular weight polymer having a weight averagemolecular weight of greater than 60 KDa (e.g., 60 KDa to 500 KDa, 60 KDato 1,000 KDa, 80 KDa to 120 KDa, 100 KDa to 300 KDa, 220 KDa to 500 KDa,or 400 KDa to 800 KDa) selected from hydroxypropyl cellulose,hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose, and methyl cellulose. In certain embodiments the second layerincludes from 6 to 65% (w/w) (e.g., 10 to 50%, 6±2%, 8±2%, 10±2%, 14±3%,18±4%, 22±5%, 25±5%, 30±5%, 35±5%, 40±5%, 45±5%, 50±5%, 55±5%, 60±5%, or65±5% (w/w)) pH neutralizing agent. In particular embodiments, the unitdosage form is a trilayer film including two outer dopamine agonistlayers, and one inner pH neutralizing layer. In particular embodiments,the dopamine agonist is selected from apomorphine, an apomorphineprodrug, bromocriptine, cabergoline, dihydroergocryptine, lisuride,piribedil, pergolide, pramipexole, rotigotine, ropinirol, and acidaddition salts thereof. In particular embodiments, the unit dosage formincludes an antioxidant, 1±0.5% glycerol monosterate, 35±5% (w/w)hydrolyzed starch, and 4±2% (w/w) pyridoxine, wherein the first layerincludes 10±5% (w/w) apomorphine hydrochloride, 2±0.75% (w/w) of a lowmolecular weight polymer having a weight average molecular weight offrom 5 KDa to 50 KDa, and 30±6% (w/w) of a high molecular weight polymerhaving a weight average molecular weight of greater than 60 KDa.

The invention features a pharmaceutical composition in unit dosage formformulated for sublingual administration, wherein the unit dosage formis a film including: (i) from 10 to 75% (w/w) (e.g., 30 to 75%, 10±5%,15±5%, 20±5%, 25±5%, 30±5%, 35±5%, 40±5%, 45±5%, 50±5%, 55±5%, 60±5%,65±5%, 70±5%, or 75±5% (w/w)) apomorphine, an apomorphine prodrug, or anacid addition salt thereof; (ii) from 0.5 to 16% (w/w) (e.g., 0.5 to10%, 0.5±0.1%, 1±0.5%, 2±0.75%, 3±1%, 5±1%, 6±2%, 7±3%, 8±3%, 9±3%,12±3%, or 16±3% (w/w)) of a low molecular weight polymer having a weightaverage molecular weight of from 5 KDa to 50 KDa (e.g., 5±3, 8±3, 10±3,15±5, 18±5, 22±6, 28±6, 34±8, 44±8, or 50±10 KDa) selected fromhydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethylcellulose, carboxymethyl cellulose, and methyl cellulose; and (iii) from4 to 35% (w/w) (e.g., 4 to 20%, 4±2%, 5±2.5%, 7.5±3%, 10±3.5%, 14±5%,18±5%, 20±6%, 25±6%, 30±6%, or 35±6% (w/w)) of a high molecular weightpolymer having a weight average molecular weight of greater than 60 KDa(e.g., 60 KDa to 500 KDa, 60 KDa to 1,000 KDa, 80 KDa to 120 KDa, 100KDa to 300 KDa, 220 KDa to 500 KDa, or 400 KDa to 800 KDa) selected fromhydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethylcellulose, carboxymethyl cellulose, and methyl cellulose. In certainembodiments the film has a surface coated with a pH neutralizing agent(e.g., a coating or dusting of an inorganic or organic base). In stillother embodiments, the unit dosage form when placed in 1 mL ofunbuffered water at pH 7 results in a solution having a pH of between2.5 and 6.5, preferably between 4.5 and 6.5, (e.g., a pH of between 2.5and 4.5, 3.0 and 6.0, 3.5 and 6.5, 4.5 and 6.5, or 5.0 and 6.0), and hasa sublingual bioavailability of greater than 40% (e.g., a sublingualbioavailability of from 40 to 70%, 45 to 85%, 55 to 95%, 65 to 100%, 70to 100%, 70 to 99%, 75 to 100%, 75 to 99%, or 80 to 99%).

In a related aspect, the invention features a pharmaceutical compositionin unit dosage form formulated for sublingual administration, whereinthe unit dosage form is a bilayer film having a first layer and a secondlayer, the first layer including: (i) from 10 to 75% (w/w) (e.g., 30 to75%, 10±5%, 15±5%, 20±5%, 25±5%, 30±5%, 35±5%, 40±5%, 45±5%, 50±5%,55±5%, 60±5%, 65±5%, 70±5%, or 75±5% (w/w)) apomorphine, an apomorphineprodrug, or an acid addition salt thereof; (ii) from 0.5 to 16% (w/w)(e.g., 0.5 to 10%, 0.5±0.1%, 1±0.5%, 2±0.75%, 3±1%, 5±1%, 6±2%, 7±3%,8±3%, 9±3%, 12±3%, or 16±3% (w/w)) of a low molecular weight polymerhaving a weight average molecular weight of from 5 KDa to 50 KDa (e.g.,5±3, 8±3%, 10±3, 15±5, 18±5, 22±6, 28±6, 34±8, 44±8, or 50±10 KDa)selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose,hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose;and (iii) from 4 to 35% (w/w) (e.g., 4 to 20%, 4±2%, 5±2.5%, 7.5±3%,10±3.5%, 14±5%, 18±5%, 20±6%, 25±6%, 30±6%, or 35±6% (w/w)) of a highmolecular weight polymer having a weight average molecular weight ofgreater than 60 KDa (e.g., 60 KDa to 500 KDa, 60 KDa to 1,000 KDa, 80KDa to 120 KDa, 100 KDa to 300 KDa, 220 KDa to 500 KDa, or 400 KDa to800 KDa) selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methylcellulose, and wherein the second layer includes a pH neutralizing agentand from 15 to 50% (w/w) (e.g., 15±5%, 20±5%, 25±5%, 30±5%, 35±5%,40±5%, 45±5%, or 50±5% (w/w)) of a high molecular weight polymer havinga weight average molecular weight of greater than 60 KDa (e.g., 60 KDato 500 KDa, 60 KDa to 1,000 KDa, 80 KDa to 120 KDa, 100 KDa to 300 KDa,220 KDa to 500 KDa, or 400 KDa to 800 KDa) selected from hydroxypropylcellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose,carboxymethyl cellulose, and methyl cellulose. In certain embodimentsthe second layer includes from 6 to 65% (w/w) (e.g., 10 to 50%, 6±2%,8±2%, 10±2%, 14±3%, 18±4%, 22±5%, 25±5%, 30±5%, 35±5%, 40±5%, 45±5%,50±5%, 55±5%, 60±5%, or 65±5% (w/w)) pH neutralizing agent. Inparticular embodiments, the unit dosage form is a trilayer filmincluding two outer apomorphine layers, and one inner pH neutralizinglayer.

In certain embodiments of the above aspects, the film further includesfrom 3 to 18% (w/w) (e.g., 3 to 12%, 3±1%, 5±2%, 7.5±2.5%, 10±3%, 12±3%,15±3%, or 18±3% (w/w)) plasticizing agent, such as a polyol (e.g.,sorbitol, mannitol, maltitol, xylitol, glycerol, propylene glycol, orpolyethylene glycol), oleic acid, or triacetin.

In particular embodiments of the above aspects, the film, or one layerof the film, further includes from 1 to 50% (w/w) (e.g., 1±0.75%,2±1.5%, 3±0.5%, 5±2%, 7.5±2.5%, 10±2%, 14±3%, 18±4%, 22±5%, 25±5%,30±5%, 35±5%, 40±5%, 45±5%, or 50±5% (w/w)) hydrolyzed starch. Thehydrolyzed starch can be a dextrin, a maltodextrin, or any hydrolyzedstarch described herein.

The films of the invention can include an antioxidant. For example, thefilms, or one layer of a bilayer film can include from 0.05 to 2.5%(w/w) (e.g., 0.05±0.025%, 0.1±0.075%, 0.3±0.1%, 0.5±0.25%, 0.75±0.25%,1±0.5%, 1.5±0.5%, 2±0.5%, or 2.5±0.5% (w/w)) metabisulfite, or anyantioxidant described herein.

The films of the invention can have a T_(max) of from 10 to 25 minutes(e.g., 9±3, 10±3, 11±3, 12±3, 13±3, 14±3, 15±3, 16±3, 17±3, 18±3, 20±3,22±3, 24±3, or 25±3 minutes).

The films of the invention can include from 0.2 to 5% (w/w) e.g.,0.5±0.25%, 0.75±0.25%, 1±0.5%, 1.5±0.5%, 2±0.5%, 2.5±0.5%, 3±0.5%,3.5±0.5%, 4±0.5%, or 5±0.5% (w/w)) of a permeation enhancer (e.g., anionic surfactant, nonionic surfactant, polysorbate, derivatives oftocopherol, poloxamer, monoglyceride, diglyceride, fatty acid, fattyalcohol, mixtures thereof, or any permeation enhancer described herein).In particular embodiments, the permeation enhancer is glycerolmonosterate.

The films of the invention can include a low molecular weight polymerselected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose,and hydroxyethyl cellulose. For example, the hydroxypropylmethylcellulose can have about 20% to about 35% methoxyl substitutionand about 5% to about 15% hydroxypropyl substitution.

The films of the invention can include a high molecular weight polymerselected from hydroxypropyl methyl cellulose and hydroxyethyl cellulose.For example, the high molecular weight polymer can be hydroxypropylmethyl cellulose having about 20% to about 35% methoxyl substitution andabout 5% to about 15% hydroxypropyl substitution. The high molecularweight polymer can be a hydroxyethyl cellulose having a weight averagemolecular weight of from 60 KDa to 1,000 KDa (e.g., 60 KDa to 500 KDa,60 KDa to 1,000 KDa, 80 KDa to 120 KDa, 100 KDa to 300 KDa, 220 KDa to500 KDa, or 400 KDa to 800 KDa).

In particular embodiments the first layer is separated from the secondlayer by a barrier (e.g., a third layer).

For films of the invention including a pH neutralizing agent, in certainembodiments the pH neutralizing agent is an inorganic base (e.g.,aluminum hydroxide, aluminosilicates, calcium hydroxide, magnesiumhydroxide, potassium hydroxide, sodium hydroxide, calcium carbonate,iron carbonate, magnesium carbonate, zinc carbonate, sodium carbonate,potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodiumphosphate monobasic, sodium phosphate dibasic, sodium phosphatetribasic, potassium phosphate monobasic, potassium phosphate dibasic,potassium phosphate tribasic, mixtures thereof, and any inorganic basedescribed herein). In still other embodiments, the pH neutralizing agentis an organic base (e.g., acetate salts, citrate salts, stearate salts,laurate salts, proprionate salts, lactate salts, succinate salts,oxalate salts, tartrate salts, glycolate salts, galacturonate salts,glucuronate salts, alginate salts, sorbate salts, caprylate salts,carboxymethyl cellulose, polyacrylate, and mixtures thereof and amines,such as pyridoxine, meglumine, lysine, Eudragit E, diethanolamine,glycine, citrate, acetate, histidine, N-methyl glucamine, andtris(hydroxymethyl)aminomethane, mixtures thereof, or any organic basedescribed herein). In particular embodiments, the base has a pKa of from2.5 to 9.5 (e.g., a pKa of 2±0.5, 2.5±1, 3±1.5, 4±2, 5±2, 6±2, 7±1, or apKa of from 4.5 to 8.5).

In a related aspect, the invention features a kit including: (i) amonolayer film of the invention; (ii) a pH neutralizing agent; and (iii)instructions for administering the first film and the pH neutralizingagent simultaneously to a subject.

The sublingual formulations can include dopamine agonist particleshaving an effective particle size of from 0.5 μm to 50 μm (e.g., aneffective particle size of from 1 μm to 10 μm, 1 μm to 9 μm, from 1 μmto 8 μm, from 1 μm to 7 μm, from 1 μm to 6 μm, from 1 μm to 5 μm, from 2μm to 10 μm, from 3 μm to 10 μm, from 4 μm to 10 μm, from 2 μm to 7 μm,2 μm to 6 μm, 0.5 μm to 25 μm, 0.5 μm to 20 μm, or from 5 μm to 12 μm).In particular embodiments, the formulations include dopamine agonistparticles containing apomorphine, an apomorphine prodrug, bromocriptine,cabergoline, dihydroergocryptine, lisuride, piribedil, pergolide,pramipexole, rotigotine, ropinirol, or particles formed from their acidaddition salts.

The sublingual formulations can include dopamine agonist particleshaving an effective particle size of from 10 μm to 100 μm (e.g., aneffective particle size of from 10 μm to 90 μm, from 10 μm to 80 μm,from 10 μm to 70 μm, from 10 μm to 60 μm, from 10 μm to 50 μm, from 20μm to 100 μm, from 30 μm to 100 μm, from 40 μm to 100 μm, from 20 μm to70 μm, or from 20 μm to 60 μm). In particular embodiments, theformulations include dopamine agonist particles containing apomorphine,an apomorphine prodrug, bromocriptine, cabergoline, dihydroergocryptine,lisuride, piribedil, pergolide, pramipexole, rotigotine, ropinirol, orparticles formed from their acid addition salts.

In certain other embodiments, the sublingual formulations can includedopamine agonist particles having an effective particle size of from 20nm to 1 μm (e.g., an effective particle size of from 20 nm to 1 μm, from40 nm to 1 μm, from 60 nm to 1 μm, from 80 nm to 1 μm, from 100 nm to 1μm, from 20 nm to 800 nm, from 20 nm to 700 nm, from 50 nm to 700 nm,from 40 nm to 800 nm, from 60 nm to 800 nm, from 100 nm to 800 nm, from60 nm to 700 nm, from 60 nm to 600 nm, from 100 nm to 600 nm, from 150nm to 800 nm, or from 150 nm to 600 nm). In particular embodiments, theformulations include dopamine agonist particles containing apomorphine,an apomorphine prodrug, bromocriptine, cabergoline, dihydroergocryptine,lisuride, piribedil, pergolide, pramipexole, rotigotine, ropinirol, orparticles formed from their acid addition salts.

The sublingual formulations can include apomorphine particles having aneffective particle size of from 0.5 μm to 50 μm (e.g., an effectiveparticle size of from 1 μm to 10 μm, 1 μm to 9 μm, from 1 μm to 8 μm,from 1 μm to 7 μm, from 1 μm to 6 μm, from 1 μm to 5 μm, from 2 μm to 10μm, from 3 μm to 10 μm, from 4 μm to 10 μm, from 2 μm to 7 μm, 2 μm to 6μm, 0.5 μm to 25 μm, 0.5 μm to 20 μm, or from 5 μm to 12 μm).

The sublingual formulations can include apomorphine particles having aneffective particle size of from 10 μm to 100 μm (e.g., an effectiveparticle size of from 10 μm to 90 μm, from 10 μm to 80 μm, from 10 μm to70 μm, from 10 μm to 60 μm, from 10 μm to 50 μm, from 20 μm to 100 μm,from 30 μm to 100 μm, from 40 μm to 100 μm, from 20 μm to 70 μm, or from20 μm to 60 μm).

In certain other embodiments, the sublingual formulations can includeapomorphine particles having an effective particle size of from 20 nm to1 μm (e.g., an effective particle size of from 20 nm to 1 μm, from 40 nmto 1 μm, from 60 nm to 1 μm, from 80 nm to 1 μm, from 100 nm to 1 μm,from 20 nm to 800 nm, from 20 nm to 700 nm, from 50 nm to 700 nm, from40 nm to 800 nm, from 60 nm to 800 nm, from 100 nm to 800 nm, from 60 nmto 700 nm, from 60 nm to 600 nm, from 100 nm to 600 nm, from 150 nm to800 nm, or from 150 nm to 600 nm).

In another aspect, the invention features a pharmaceutical compositionin unit dosage form formulated for sublingual administration, the unitdosage form including from 2 to 60 mg of an apomorphine prodrug (e.g.,from 2 to 15 mg, 10 to 50 mg, 12 to 30 mg, 20 to 50 mg, 15 to 30 mg, or35 to 50 mg of an apomorphine prodrug) in the form of apomorphineparticles having an effective particle size of from 10 μm to 100 μm(e.g., an effective particle size of from 10 μm to 90 μm, from 10 μm to80 μm, from 10 μm to 70 μm, from 10 μm to 60 μm, from 10 μm to 50 μm,from 20 μm to 100 μm, from 30 μm to 100 μm, from 40 μm to 100 μm, from20 μm to 70 μm, or from 20 μm to 60 μm). The unit dosage form can be alozenge, a pill, a tablet, a film, or strip including from theapomorphine prodrug in its free base form. In still other embodiments,the unit dosage form is a film formulation described herein.

In still another aspect, the invention features a pharmaceuticalcomposition in unit dosage form formulated for sublingualadministration, the unit dosage form including dopamine agonistparticles having an effective particle size of from 10 μm to 100 μm(e.g., an effective particle size of from 10 μm to 90 μm, from 10 μm to80 μm, from 10 μm to 70 μm, from 10 μm to 60 μm, from 10 μm to 50 μm,from 20 μm to 100 μm, from 30 μm to 100 μm, from 40 μm to 100 μm, from20 μm to 70 μm, or from 20 μm to 60 μm). The unit dosage form can be alozenge, a pill, a tablet, a film, or strip including from the dopamineagonist in its free base form. In still other embodiments, the unitdosage form is a film formulation described herein. In particularembodiments, the formulations include dopamine agonist particlescontaining apomorphine, an apomorphine prodrug, bromocriptine,cabergoline, dihydroergocryptine, lisuride, piribedil, pergolide,pramipexole, rotigotine, ropinirol, or particles formed from their acidaddition salts.

In certain embodiments, the sublingual formulation includes apomorphineparticle and the apomorphine particle include an acid addition salt ofapomorphine or an apomorphine prodrug. The acid addition salt can beapomorphine hydrochloride or any acid addition salt described herein.Alternatively, the acid addition salt can be the hydrochloride salt ofan apomorphine prodrug or any other acid addition salt described herein.

In an embodiment of any of the above pharmaceutical compositions, thepharmaceutical composition is in a unit dosage form including from 0.1to 100 mg or 2 to 60 mg of apomorphine, an apomorphine prodrug, or anacid addition salt thereof (e.g., from 0.5 to 5 mg, 4 to 10 mg, 6 to 15mg, 8 to 20 mg, 10 to 25 mg, 12 to 30 mg, 20 to 35 mg, 25 to 40 mg, or30 to 40 mg of apomorphine, an apomorphine prodrug, or an acid additionsalt thereof). For example, each unit dosage form can contain 1±0.5 mg,3±1 mg, 4±1 mg, 5±1 mg, 8±2 mg, 10±3 mg, 12±3 mg, 15±3 mg, 22±4 mg, 27±4mg, 30±5 mg, 35±5 mg, 40±5 mg, 45±5 mg, 50±5 mg, 55±5 mg, or 60±5 mg ofapomorphine, an apomorphine prodrug, or an acid addition salt thereof.

In another embodiment of any of the above pharmaceutical compositions,the pharmaceutical composition is in a unit dosage form including anacid addition salt of ropinirol. In particular embodiments, thepharmaceutical composition includes the hydrochloride salt of ropinirol.

In another embodiment of any of the above pharmaceutical compositions,the pharmaceutical composition is a film including a solid solution ofan acid addition salt of the dopamine agonist (e.g., a solid solution ofapomorphine, an apomorphine prodrug, bromocriptine, cabergoline,dihydroergocryptine, lisuride, piribedil, pergolide, pramipexole,rotigotine, ropinirol, or an acid addition salt thereof).

In an embodiment of any of the above pharmaceutical compositions, thepharmaceutical composition is in a unit dosage form including from 0.1to 100 mg or 0.1 to 40 mg of ropinirol, or an acid addition salt thereof(e.g., from 0.1 to 2 mg, 1 to 5 mg, 4 to 10 mg, 6 to 15 mg, 8 to 20 mg,10 to 25 mg, 12 to 30 mg, 20 to 35 mg, 25 to 40 mg, or 30 to 40 mg ofropinirol, or an acid addition salt thereof). For example, each unitdosage form can contain 0.5±0.25 mg, 3±1 mg, 4±1 mg, 5±1 mg, 8±2 mg,10±3 mg, 12±3 mg, 15±3 mg, 22±4 mg, 27±4 mg, 30±5 mg, 35±5 mg, or 40±5mg, of ropinirol, or an acid addition salt thereof.

In an embodiment of any of the above pharmaceutical compositions, thepharmaceutical composition is in a unit dosage form including from 0.1to 100 mg or 0.2 to 20 mg of bromocriptine, or an acid addition saltthereof (e.g., from 0.2 to 2 mg, 0.5 to 3 mg, 1 to 4 mg, 3 to 7 mg, 6 to11 mg, 9 to 15 mg, 13 to 18 mg, or 16 to 20 mg of bromocriptine, or anacid addition salt thereof). For example, each unit dosage form cancontain 0.2±0.1 mg, 0.5±0.25 mg, 1±0.5 mg, 2±0.5 mg, 3±1 mg, 4±1.5 mg,6±2 mg, 10±3 mg, 14±3 mg, 18±3 mg, or 20±5 mg of bromocriptine, or anacid addition salt thereof.

In an embodiment of any of the above pharmaceutical compositions, thepharmaceutical composition is in a unit dosage form including from 0.1to 100 mg or 2 to 20 mg of cabergoline, or an acid addition salt thereof(e.g., from 0.2 to 2 mg, 0.5 to 3 mg, 1 to 4 mg, 3 to 7 mg, 6 to 11 mg,9 to 15 mg, 13 to 18 mg, or 16 to 20 mg of cabergoline, or an acidaddition salt thereof). For example, each unit dosage form can contain0.2±0.1 mg, 0.5±0.25 mg, 1±0.5 mg, 2±0.5 mg, 3±1 mg, 4±1.5 mg, 6±2 mg,10±3 mg, 14±3 mg, 18±3 mg, or 20±5 mg of cabergoline, or an acidaddition salt thereof.

In an embodiment of any of the above pharmaceutical compositions, thepharmaceutical composition is in a unit dosage form including from 0.1to 100 mg or 0.5 to 30 mg of dihydroergocryptine, or an acid additionsalt thereof (e.g., from 0.5 to 5 mg, 4 to 10 mg, 6 to 15 mg, 8 to 12mg, 10 to 15 mg, 15 to 25 mg, or 20 to 30 mg of dihydroergocryptine, oran acid addition salt thereof). For example, each unit dosage form cancontain 1±0.5 mg, 3±1 mg, 4±1 mg, 5±1 mg, 8±2 mg, 10±3 mg, 12±3 mg, 15±3mg, 22±4 mg, 27±4 mg, or 30±5 mg of dihydroergocryptine, or an acidaddition salt thereof.

In an embodiment of any of the above pharmaceutical compositions, thepharmaceutical composition is in a unit dosage form including from 0.1to 100 mg or 0.05 to 10 mg of lisuride, or an acid addition salt thereof(e.g., from 0.05 to 0.5 mg, 0.4 to 1 mg, 0.8 to 1.5 mg, 1 to 2 mg, 1.5to 3 mg, 2.5 to 5 mg, or 5 to 10 mg of lisuride, or an acid additionsalt thereof). For example, each unit dosage form can contain 0.1±0.05mg, 0.3±0.1 mg, 0.4±0.1 mg, 0.5±0.1 mg, 1±0.5 mg, 2±1 mg, 3±1 mg, 5±2mg, 7±2 mg, 9±2 mg, or 10±2 mg of lisuride, or an acid addition saltthereof.

In an embodiment of any of the above pharmaceutical compositions, thepharmaceutical composition is in a unit dosage form including from 0.1to 100 mg or 0.5 to 75 mg of piribedil, or an acid addition salt thereof(e.g., from 0.5 to 5 mg, 4 to 10 mg, 6 to 15 mg, 8 to 12 mg, 10 to 15mg, 15 to 25 mg, 20 to 30 mg, 35 to 45 mg, 40 to 50 mg, or 50 to 75 mgof piribedil, or an acid addition salt thereof). For example, each unitdosage form can contain 1±0.5 mg, 3±1 mg, 4±1 mg, 5±1 mg, 8±2 mg, 10±3mg, 12±3 mg, 15±3 mg, 22±4 mg, 27±4 mg, 30±5 mg, 40±10 mg, 50±10 mg, or75±20 mg of piribedil, or an acid addition salt thereof.

In an embodiment of any of the above pharmaceutical compositions, thepharmaceutical composition is in a unit dosage form including from 0.1to 100 mg or 0.05 to 10 mg of pergolide, or an acid addition saltthereof (e.g., from 0.05 to 0.5 mg, 0.4 to 1 mg, 0.8 to 1.5 mg, 1 to 2mg, 1.5 to 3 mg, 2.5 to 5 mg, or 5 to 10 mg of pergolide, or an acidaddition salt thereof). For example, each unit dosage form can contain0.1±0.05 mg, 0.3±0.1 mg, 0.4±0.1 mg, 0.5±0.1 mg, 1±0.5 mg, 2±1 mg, 3±1mg, 5±2 mg, 7±2 mg, 9±2 mg, or 10±2 mg of pergolide, or an acid additionsalt thereof.

In an embodiment of any of the above pharmaceutical compositions, thepharmaceutical composition is in a unit dosage form including from 0.1to 100 mg or 0.1 to 20 mg of pramipexole, or an acid addition saltthereof (e.g., from 0.1 to 0.5 mg, 0.2 to 2 mg, 0.5 to 3 mg, 1 to 4 mg,3 to 7 mg, 6 to 11 mg, 9 to 15 mg, 13 to 18 mg, or 16 to 20 mg ofpramipexole, or an acid addition salt thereof). For example, each unitdosage form can contain 0.2±0.1 mg, 0.5±0.25 mg, 1±0.5 mg, 2±0.5 mg, 3±1mg, 4±1.5 mg, 6±2 mg, 10±3 mg, 14±3 mg, 18±3 mg, or 20±5 mg ofpramipexole, or an acid addition salt thereof.

In an embodiment of any of the above pharmaceutical compositions, thepharmaceutical composition is in a unit dosage form including from 0.1to 100 mg or 0.1 to 20 mg of rotigotine, or an acid addition saltthereof (e.g., from 0.1 to 0.5 mg, 0.2 to 2 mg, 0.5 to 3 mg, 1 to 4 mg,3 to 7 mg, 6 to 11 mg, 9 to 15 mg, 13 to 18 mg, or 16 to 20 mg ofrotigotine, or an acid addition salt thereof). For example, each unitdosage form can contain 0.2±0.1 mg, 0.5±0.25 mg, 1±0.5 mg, 2±0.5 mg, 3±1mg, 4±1.5 mg, 6±2 mg, 10±3 mg, 14±3 mg, 18±3 mg, or 20±5 mg ofrotigotine, or an acid addition salt thereof.

In a particular embodiment of any of the above pharmaceuticalcompositions, the unit dosage form when administered sublingually to asubject is non-irritating.

In still another embodiment of any of the above pharmaceuticalcompositions wherein the dopamine agonist is selected from apomorphine,an apomorphine prodrug, or a salt thereof, following sublingualadministration to a subject the unit dosage form produces an averagecirculating apomorphine concentration of at least 3 ng/mL within aperiod of from 5 to 15 minutes following the administration. Forexample, the unit dosage form can produce an average circulatingconcentration of from 3 to 6 ng/mL within 7 to 10 minutes, from 5 to 10ng/mL within 5 to 10 minutes, from 7 to 12 ng/mL within 5 to 10 minutes,from 10 to 16 ng/mL within 5 to 10 minutes, from 3 to 6 ng/mL within 7to 15 minutes, from 5 to 10 ng/mL within 7 to 15 minutes, from 7 to 12ng/mL within 7 to 15 minutes, from 10 to 16 ng/mL within 7 to 15minutes, from 3 to 6 ng/mL within 15 to 20 minutes, from 5 to 10 ng/mLwithin 15 to 20 minutes, from 7 to 12 ng/mL within 15 to 20 minutes, orfrom 10 to 16 ng/mL within 15 to 20 minutes following theadministration.

In another embodiment of any of the above pharmaceutical compositions,the unit dosage form when placed in 1 mL of unbuffered water at pH 7results in a solution having a pH of between 2.5 and 8.0, preferablybetween 4.5 and 6.5, (e.g., a pH of between 2.5 and 4.5, 3.0 and 6.5,3.5 and 7.5, 4.5 and 8.0, or 6.5 and 8.0). For example, the films of theinvention can include a neutralizing layer that controls the pH of thedissolved pharmaceutical composition and produces a predetermined pHvalue upon dissolution.

In another embodiment of any of the above pharmaceutical compositions,the unit dosage form has a sublingual bioavailability of greater than ofgreater than 40% (e.g., a sublingual bioavailability of from 40 to 70%,45 to 85%, 55 to 95%, 65 to 100%, 70 to 100%, 70 to 99%, 75 to 100%, 75to 99%, or 80 to 99%).

The invention further features a method of treating movement disorders,such as Parkinson's disease, restless leg syndrome, or tremor, in asubject by sublingually administering a pharmaceutical composition ofthe invention to the subject in an amount effective to treat thesubject.

The invention also features a method for alleviating dyskinesia in asubject afflicted with Parkinson's disease by sublingually administeringa pharmaceutical composition of the invention to the subject in anamount effective to alleviate the dyskinesia.

The invention also features a method for alleviating akinesia in asubject afflicted with Parkinson's disease by sublingually administeringa pharmaceutical composition of the invention to the subject in anamount effective to alleviate the akinesia.

The invention features a method of treating sexual dysfunction in asubject by sublingually administering a pharmaceutical composition ofthe invention to the subject in an amount effective to treat thesubject.

The invention also features a method of treating a depressive disorderin a subject by sublingually administering a pharmaceutical compositionof the invention to the subject in an amount effective to treat thesubject.

In one embodiment of any of the above methods, the method furtherincludes administration of an effective amount of an anti-emetic agent(e.g., nicotine, lobeline sulfate, pipamazine, oxypendyl hydrochloride,ondansetron, buclizine hydrochloride, cyclizine hydrochloride,dimenhydrinate, scopolamine, metopimazine, benzauinamine hydrochloride,or diphenidol hydrochloride).

The invention feature a method of preparing a bilayer film having afirst layer and a second layer, the method including:

(i) forming a first viscous solution by mixing an aqueous solutionincluding a volatile organic solvent with (a) from 30 to 75% (w/w)(e.g., 30±5%, 35±5%, 40±5%, 45±5%, 50±5%, 55±5%, 60±5%, 65±5%, 70±5%, or75±5% (w/w)) dopamine agonist, or an acid addition salt thereof (e.g.,apomorphine, an apomorphine prodrug, bromocriptine, cabergoline,dihydroergocryptine, lisuride, piribedil, pergolide, pramipexole,rotigotine, ropinirol, or an acid addition salt thereof); (b) from 0.5to 16% (w/w) (e.g., 0.5 to 10%, 0.5±0.1%, 1±0.5%, 2±0.75%, 3±1%, 5±1%,6±2%, 7±3%, 8±3%, 9±3%, 12±3%, or 16±3% (w/w)) of a low molecular weightpolymer having a weight average molecular weight of from 5 KDa to 50 KDa(e.g., 5±3, 8±3%, 10±3, 15±5, 18±5, 22±6, 28±6, 34±8, 44±8, or 50±10KDa) selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methylcellulose; (c) from 4 to 35% (w/w) (e.g., 4 to 20%, 4±2%, 5±2.5%,7.5±3%, 10±3.5%, 14±5%, 18±5%, 20±6%, 25±6%, 30±6%, or 35±6% (w/w)) of ahigh molecular weight polymer having a weight average molecular weightof greater than 60 KDa (e.g., 60 KDa to 500 KDa, 60 KDa to 1,000 KDa, 80KDa to 120 KDa, 100 KDa to 300 KDa, 220 KDa to 500 KDa, or 400 KDa to800 KDa) selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methylcellulose; (d) from 3 to 18% (w/w) (e.g., 3 to 12%, 3±1%, 5±2%,7.5±2.5%, 10±3%, 12±3%, 15±3%, or 18±3% (w/w)) of a plasticizing agent;and (e) from 1 to 50% (w/w) (e.g., 1±0.75%, 2±1.5%, 3±0.5%, 5±2%,7.5±2.5%, 10±2%, 14±3%, 18±4%, 22±5%, 25±5%, 30±5%, 35±5%, 40±5%, 45±5%,or 50±5% (w/w)) hydrolyzed starch;

(ii) casting the first viscous solution onto an inert support, anddrying the solution to form a first film layer;

(iii) forming a second viscous solution by mixing an aqueous solutionincluding a volatile organic solvent with (a) from 15 to 50% (w/w)(e.g., 15±5%, 20±5%, 25±5%, 30±5%, 35±5%, 40±5%, 45±5%, or 50±5% (w/w))of a high molecular weight polymer having a weight average molecularweight of greater than 60 KDa (e.g., 60 KDa to 500 KDa, 60 KDa to 1,000KDa, 80 KDa to 120 KDa, 100 KDa to 300 KDa, 220 KDa to 500 KDa, or 400KDa to 800 KDa) selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, andmethyl cellulose; (b) from 6 to 65% (w/w) (e.g., 10 to 50%, 6±2%, 8±2%,10±2%, 14±3%, 18±4%, 22±5%, 25±5%, 30±5%, 35±5%, 40±5%, 45±5%, 50±5%,55±5%, 60±5%, or 65±5% (w/w)) pH neutralizing agent; (c) from 3 to 18%(w/w) (e.g., 3 to 12%, 3±1%, 5±2%, 7.5±2.5%, 10±3%, 12±3%, 15±3%, or18±3% (w/w)) of a plasticizing agent; and (d) from 1 to 50% (w/w) (e.g.,1±0.75%, 2±1.5%, 3±0.5%, 5±2%, 7.5±2.5%, 10±2%, 14±3%, 18±4%, 22±5%,25±5%, 30±5%, 35±5%, 40±5%, 45±5%, or 50±5% (w/w)) hydrolyzed starch;

(iv) casting the second viscous solution onto an inert support, anddrying the solution to form a second film layer;

(v) contacting faces of the first film layer and the second film layerwith a volatile organic solvent, pressing the faces together such thatvolatile organic solvent is sandwiched between the first film layer andthe second film layer, and drying the layers to form a bilayer film.

The invention feature a method of preparing a bilayer film having afirst layer and a second layer, the method including:

(i) forming a first viscous solution by mixing an aqueous solutionincluding a volatile organic solvent with (a) from 30 to 75% (w/w)(e.g., 30±5%, 35±5%, 40±5%, 45±5%, 50±5%, 55±5%, 60±5%, 65±5%, 70±5%, or75±5% (w/w)) apomorphine, an apomorphine prodrug, or an acid additionsalt thereof; (b) from 0.5 to 16% (w/w) (e.g., 0.5 to 10%, 0.5±0.1%,1±0.5%, 2±0.75%, 3±1%, 5±1%, 6±2%, 7±3%, 8±3%, 9±3%, 12±3%, or 16±3%(w/w)) of a low molecular weight polymer having a weight averagemolecular weight of from 5 KDa to 50 KDa (e.g., 5±3, 8±3%, 10±3, 15±5,18±5, 22±6, 28±6, 34±8, 44±8, or 50±10 KDa) selected from hydroxypropylcellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose,carboxymethyl cellulose, and methyl cellulose; (c) from 4 to 35% (w/w)(e.g., 4 to 20%, 4±2%, 5±2.5%, 7.5±3%, 10±3.5%, 14±5%, 18±5%, 20±6%,25±6%, 30±6%, or 35±6% (w/w)) of a high molecular weight polymer havinga weight average molecular weight of greater than 60 KDa (e.g., 60 KDato 500 KDa, 60 KDa to 1,000 KDa, 80 KDa to 120 KDa, 100 KDa to 300 KDa,220 KDa to 500 KDa, or 400 KDa to 800 KDa) selected from hydroxypropylcellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose,carboxymethyl cellulose, and methyl cellulose; (d) from 3 to 18% (w/w)(e.g., 3 to 12%, 3±1%, 5±2%, 7.5±2.5%, 10±3%, 12±3%, 15±3%, or 18±3%(w/w)) of a plasticizing agent; and (e) from 1 to 50% (w/w) (e.g.,1±0.75%, 2±1.5%, 3±0.5%, 5±2%, 7.5±2.5%, 10±2%, 14±3%, 18±4%, 22±5%,25±5%, 30±5%, 35±5%, 40±5%, 45±5%, or 50±5% (w/w)) hydrolyzed starch;

(ii) casting the first viscous solution onto an inert support, anddrying the solution to form a first film layer;

(iii) forming a second viscous solution by mixing an aqueous solutionincluding a volatile organic solvent with (a) from 15 to 50% (w/w)(e.g., 15±5%, 20±5%, 25±5%, 30±5%, 35±5%, 40±5%, 45±5%, or 50±5% (w/w))of a high molecular weight polymer having a weight average molecularweight of greater than 60 KDa (e.g., 60 KDa to 500 KDa, 60 KDa to 1,000KDa, 80 KDa to 120 KDa, 100 KDa to 300 KDa, 220 KDa to 500 KDa, or 400KDa to 800 KDa) selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, andmethyl cellulose; (b) from 6 to 65% (w/w) (e.g., 10 to 50%, 6±2%, 8±2%,10±2%, 14±3%, 18±4%, 22±5%, 25±5%, 30±5%, 35±5%, 40±5%, 45±5%, 50±5%,55±5%, 60±5%, or 65±5% (w/w)) pH neutralizing agent; (c) from 3 to 18%(w/w) (e.g., 3 to 12%, 3±1%, 5±2%, 7.5±2.5%, 10±3%, 12±3%, 15±3%, or18±3% (w/w)) of a plasticizing agent; and (d) from 1 to 50% (w/w) (e.g.,1±0.75%, 2±1.5%, 3±0.5%, 5±2%, 7.5±2.5%, 10±2%, 14±3%, 18±4%, 22±5%,25±5%, 30±5%, 35±5%, 40±5%, 45±5%, or 50±5% (w/w)) hydrolyzed starch;

(iv) casting the second viscous solution onto an inert support, anddrying the solution to form a second film layer;

(v) contacting faces of the first film layer and the second film layerwith a volatile organic solvent, pressing the faces together such thatvolatile organic solvent is sandwiched between the first film layer andthe second film layer, and drying the layers to form a bilayer film.

The volatile organic solvent (e.g., an organic solvent having a boilingpoint of between 20° C. and 80° C.) can include acetone, ethanol,isopropyl alcohol, diethyl ether, butanol, propanol, ethyl acetate, orcombinations thereof.

In certain embodiments of the method, the plasticizing agent is a polyol(e.g., sorbitol, mannitol, maltitol, xylitol, glycerol, propyleneglycol, or polyethylene glycol), oleic acid, or triacetin. In particularembodiments of the method, the hydrolyzed starch is a dextrin or amaltodextrin. The method can be used to produce any bilayer film of theinvention described herein.

In still other embodiments of the method, the dopamine agonist isapomorphine or apomorphine prodrug. For example, the apomorphine orapomorphine prodrug can be an acid addition salt of apomorphine, such asapomorphine hydrochloride. The apomorphine hydrochloride can be milledto produce material having an effective particle size of from 0.5 μm to50 μm (e.g., an effective particle size of from 1 μm to 10 μm, 1 μm to 9μm, from 1 μm to 8 μm, from 1 μm to 7 μm, from 1 μm to 6 μm, from 1 μmto 5 μm, from 2 μm to 10 μm, from 3 μm to 10 μm, from 4 μm to 10 μm,from 2 μm to 7 μm, 2 μm to 6 μm, 0.5 μm to 25 μm, 0.5 μm to 20 μm, orfrom 5 μm to 12 μm) prior to the addition of the apomorphinehydrochloride to the mixture of step (i).

In an embodiment of any of the above methods and compositions in whichthe dopamine agonist includes apomorphine or apomorphine prodrug, theapomorphine, apomorphine prodrug, or salt thereof is a racemic mixtureof R and S isomers, or enriched in R isomer (i.e., the ratio of R to Sisomer for all of the apomorphine in the composition, or all theapomorphine being administered, is from 5:1 to 1,000:1, from 10:1 to10,000:1, or from 100:1 to 100,000:1, or over all apomorphine isomers inthe composition is at least 98% R isomer, 99% R isomer, 99.5% R isomer,99.9% R isomer, or is free of any observable amount of S isomer.

The term “administration” or “administering” refers to a method ofgiving a sublingual dosage of dopamine agonist to a patient.

As used herein, the term “apomorphine particle” refers to microparticlesor nanoparticles containing apomorphine, an apomorphine prodrug, orsalts thereof.

As used herein, the term “dopamine agonist particle” refers tomicroparticles or nanoparticles containing a dopamine agonist (e.g.,apomorphine, an apomorphine prodrug, bromocriptine, cabergoline,dihydroergocryptine, lisuride, piribedil, pergolide, pramipexole,rotigotine, ropinirol, or an acid addition salt thereof).

As used herein, the term “average circulating concentration” refers tothe average plasma concentration of apomorphine at time t observed for agroup of subjects following sublingual administration of a particularunit dosage form of the invention. For example, among 20 subjects theaverage circulating concentration of apomorphine 10 minutes followingsublingual administration of the unit dosage form can be at least 3ng/mL, 5 ng/mL, 7 ng/mL, 9 ng/mL, 11 ng/mL, 13 ng/mL, or 15 ng/mL,depending upon the amount of apomorphine in the unit dosage.

By “depressive disorder” is meant any psychological or psychiatricdisorder associated with symptoms of depressed mood. Treatabledepressive disorders may be characterized by an inhibition or reductionof dopaminergic function in the nucleus accumbens, e.g., majordepression, dysthymia, bipolar disorder (manic depression), andpost-traumatic stress disorder.

As used herein, the terms “effective particle size” and “particle size”are used interchangeably and refer to a mixture of particles having adistribution in which 50% of the particles are below and 50% of theparticles are above a defined measurement. The “effective particle size”refers to the volume-weighted median diameter as measured by alaser/light scattering method or equivalent, wherein 50% of theparticles, by volume, have a smaller diameter, while 50% by volume havea larger diameter. The effective particle size can be measured byconventional particle size measuring techniques well known to thoseskilled in the art. Such techniques include, for example, sedimentationfield flow fractionation, photon correlation spectroscopy, lightscattering (e.g., with a Microtrac UPA 150), laser diffraction, and disccentrifugation.

As used herein, the term “apomorphine prodrug” refers to apomorphineesters and glycosides of formula (I):

and acid addition salts thereof. In formula I, each of R¹ and R² is,independently, H, C(O)—R₃, C(O)—O—R₃, or a glycoside of a monosaccharideor oligosaccharide; or R¹ and R² combine with the oxygen atoms to whichthey are bound to form a cyclic acetal, cyclic ketal, a cyclic carbonate(i.e., —C(O)—O—C(O)—), or an orthoester glycoside; and R₃ is a cyclic,straight chained, or branched hydrocarbon of 1 to 12 carbon atoms, whichis optionally saturated (i.e., a C₁₋₁₂ alkyl), includes one or morecarbon-carbon double bonds (i.e., a C₂₋₁₂ alkenyl), and/or includes oneor more carbon-carbon triple bonds (i.e., a C₂₋₁₂ alkynyl). For example,the apomorphine glycosides can be glycosides of straight or branchedchain glycosidic moiety containing 1-20 glycosidic units. Apomorphineglycosides and orthoester glycosides can be synthesized as described inPCT Publication No. WO/2003/080074. Apomorphine esters, cyclic acetals,and cyclic ketals can be synthesized using methods analogous to thosedescribed in U.S. Pat. No. 4,687,773, Borgman et al., J. Med. Chem.,19:717 (1976), and PCT Publication No. WO/2005/099702. The above patentpublications are incorporated herein by reference. Carbonate esters ofapomorphine can be prepared as described in Atkinson et al., J. Pharma.Sci. 65:1685 (1976), and in Campbell et al., Neuropharmacology 21:953(1982). Apomorphine prodrugs which can be used in the unit dosage formsof the invention include, without limitation, O,O′-diacetylapomorphine,O,O′-dipropionylapomorphine, O,O′-diisobutyrylapomorphine,O,O′-dipivaloylapomorphine, O,O′-dibenzoylapomorphine, apomorphinecarbonate, apomorphine diethylcarbonate, apomorphine methylene acetal,apomorphine ethyl acetal, apomorphine dimethyl acetal, and acid additionsalts thereof.

As used herein, the term “non-irritating” refers to pharmaceuticalcompositions of the invention which, using the irritation test describedin Example 7, either: (i) following administration to un-abraded cheekexhibit irritation that is equal to or less than that observed for anunbuffered acidic control film that produces a local pH of less than 3following administration to, and dissolution in, a cheek pouch; and/or(ii) following administration to abraded cheek exhibit a healing timethat is equal to or less than that observed for an unbuffered acidiccontrol film that produces a local pH of less than 3 followingadministration to, and dissolution in, a cheek pouch.

As used herein, “pH neutralizing agent” refers to any basic componentpresent in the unit dosage forms of the invention. The pH neutralizingagents which can be used in the unit dosage forms of the inventioninclude organic bases (e.g., amines), inorganic bases (e.g., oxides,hydroxides, carbonates, or phosphates), and mixtures thereof. The pHneutralizing agent is typically present in an amount sufficient toproduce a solution having a pH of between 2.5 and 8.0, preferablybetween 4.5 and 6.5, when the unit dosage form is placed in 1 mL ofunbuffered water at pH 7.

As used herein, “sexual dysfunction” refers to disorders of orgasm,response timing, ejaculation, nociception, congestive arousal anderection, vasculogenic impairment, or desire. In males, the form ofsexual dysfunction is typically erectile dysfunction, the inability toachieve and sustain an erection sufficient for intercourse. Females alsocan have sexual dysfunctions of arousal and orgasm that increase withage and are associated with the presence of vascular risk factors andonset of menopause. Some of the vascular and muscular mechanisms thatcontribute to penile erection in the male are believed to involvesimilar vasculogenic factors in female genital responses. Female sexualdysfunction includes a failure to attain or maintain vaginallubrication-swelling responses of sexual excitement until completion ofthe sexual activity.

As used herein, the term “sublingual bioavailability” refers to theaverage sublingual bioavailability of dopamine agonist formulated asdescribed herein and administered sublingually in a study of 5 or morerabbits in comparison to 100% bioavailability for subcutaneouslyadministered dopamine agonist. Sublingual bioavailability can bedetermined from a pharmacokinetic study as described in Example 2.

As used herein, the term “T_(max)” refers to the average time, followingsublingual administration of a dopamine agonist formulated as described,to the maximum circulating concentration in a study of 5 or morerabbits. T_(max) can be determined from a pharmacokinetic study asdescribed in Example 2.

As used herein, the term “treating” refers to administering apharmaceutical composition for prophylactic and/or therapeutic purposes.To “prevent disease” refers to prophylactic treatment of a patient whois not yet ill, but who is susceptible to, or otherwise at risk of, aparticular disease. To “treat disease” or use for “therapeutictreatment” refers to administering treatment to a patient alreadysuffering from a disease to ameliorate the disease and improve thepatient's condition. Thus, in the claims and embodiments, treating isthe administration to a subject either for therapeutic or prophylacticpurposes.

Other features and advantages of the invention will be apparent from thefollowing Detailed Description, the Drawings, and the Claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph depicting the pharmacokinetic profile for films A, B,and C in comparison to subcutaneously administered apomorphine (seeExamples 1 and 2).

FIG. 2 is a graph depicting the pharmacokinetic profile for films D andE in comparison to subcutaneously administered apomorphine (see Examples1 and 2).

FIG. 3 is a graph depicting the pharmacokinetic profile for films F, G,and H in comparison to subcutaneously administered apomorphine (seeExamples 1 and 2).

FIG. 4 is a graph depicting the pharmacokinetic profile for films J andK in comparison to subcutaneously administered apomorphine (see Examples1 and 2).

DETAILED DESCRIPTION

The invention features sublingual formulations of dopamine agonists. Theformulations can be useful for the treatment of Parkinson's disease,restless leg syndrome, tremors (among other movement disorders), sexualdysfunction, and depressive disorders therewith. The films can be asingle layer or a bilayer (e.g., a unit dosage form having a first layerincluding an acid addition salt of apomorphine, or an apomorphineprodrug, and a second layer including a pH neutralizing agent).

Fluctuations in motor disability and dyskinesias are a significantproblem in the long-term treatment of Parkinson's disease. In the laterstages of Parkinson's disease, many patients develop severe “off”episodes where, despite continuing to take their medication, theyexperience periods when they lose the ability to move (e.g., thepatients develop bradykinesia (slowed movement) or akinesia (inabilityto move)). These “off” episodes typically occur 3 to 4 times per day.

Apomorphine has a rapid onset of action which is ideal for use as arescue therapy for intractable “off” periods in Parkinson's disease.Other dopamine agonists can also be useful.

Using the sublingual formulations of the invention, a subject sufferingfrom the effects of middle stage or late stage Parkinson's disease maybe able to recognize the onset of their “off” symptoms and be capable ofadministering a sublingual dose of a formulation of the invention toalleviate the dyskinesia associated with such “off” episodes. Thesublingual formulations are easy for a subject with compromised motorskills to administer and can relieve a Parkinson's patient from the needfor a caregiver, who might otherwise be needed to administer aninjectable dosage form of apomorphine at the onset of an “off” episode.

The sublingual formulations of the invention can increase thebioavailability of the dopamine agonist, prolong the stability, incertain cases, of the dopamine agonist, and/or improve the safety andefficacy of the dopamine agonist therapy. The formulations can produce arapid uptake of the dopamine agonist into the subject, allowingdyskinesia episodes to be self-treated. Furthermore, the conveniencewith which these sublingual formulations can be self administeredprovides a significant advantage to severely ill patients, such as thosewith middle stage or late stage Parkinson's disease.

The pharmaceutical compositions of the invention can provide arapid-dissolving, rapid absorption solid oral dosage form that includes(i) an acid salt form of a dopamine agonist and (ii) a pH-modifyingagent. Typically, the acid addition salt has high water solubility,which assists in achieving fast dissolution, a pre-requisite to fastabsorption. Passive transcellular absorption is the primary route ofabsorption for dopamine agonists in the sublingual cavity. Passiveabsorption occurs by partition of the neutral, free-base or unionizedform of the dopamine agonist into the tissues and through cellularmembranes and is therefore partially determined by the 2 key factors:(i) the abundance of the neutral dopamine agonist species which isdriven by an equilibrium of the ionized form (salt form) and thenon-ionized form which is a function of the local pH and the pKa of thedopamine agonist; and (ii) the lipophilicity of the neutral dopamineagonist species. The inclusion of the pH-modifying agent helps tomaintain a pH and favor deprotonation of the ionized form (salt form),thus, increasing the fraction of non-ionized species and increasing therate of absorption.

Another benefit of the formulations of the invention is that they can benon-irritating at the site of administration. Irritation duringsublingual or nasal delivery of a dopamine agonist is believed to arisein some instances because of absorption of the neutral form of thedopamine agonist in the absence of a pH-modifier. Passive trans-cellularabsorption of the neutral species from the natural equilibrium ofionized and non-ionized species causes a displacement of the sameequilibrium to replenish the solution concentration of the neuraldopamine agonist species. In theory, such a displacement could lead todepletion of the agonist from solution, resulting in the release of theacid and a reduction in the local pH. The lower pH in turn can causelocal irritation, especially in the case of repeated dosing, chronicadministration.

Additional details of how to make and use the sublingual formulations ofthe invention are provided below and in the Examples.

Dopamine Agonists

Dopamine agonists which can be used in the compositions and methods ofthe invention include, without limitation, ergot and non-ergot dopamineagonists, such apomorphine, bromocriptine, cabergoline,dihydroergocryptine, lisuride, piribedil, pergolide, pramipexole,rotigotine, ropinirol, and acid addition salts thereof. The dopamineagonists can be formulated as described in the Examples.

Monolayer and Bilayer Films

The films of the invention are not dissimilar to the films used, forexample, to make the Listerine® PocketPak® mouth fresheners.

The films can include one layer, two layers, or more. If in two layers,the one adapted to adhere to mucosal tissue may be referred to as the“adhesive layer.” With two layers, the outer layer can be less adhesiveor non-adhesive, and can provide protection against mechanicalagitation, such as agitation by a user's tongue. The components of theouter layer might be, of themselves, less dissolvable than thecomponents of an adhesive layer. However, in the aggregate, the filmshall dissolve in that it will transition to fully dissolved parts orparts that will be carried away by normal cleaning processes at themucosal tissue in question. In forming two layers, diffusion or theforming process itself may provide a gradient in component amounts inthe transition between the two layers. The two layers can be utilized toseparate components (e.g., a dopamine agonist-containing acidic layerand a buffered pH neutralizing layer), which together can enhanceabsorption, reduce irritation, and/or improve stability of the dopamineagonist, but which may otherwise be incompatible in certain formulationsrequiring long term stability (i.e., shelf life). The two componentlayers of the bilayer can be laminated together using combinations ofwater, heat, solvent and aqueous, organic or mixed aqueous-organicsolutions containing any one or combination of polymer(s), low molecularweight sugar(s), stabilizer(s), flavor(s), sweetner(s), permeationenhancer(s) or other desirable agent.

Alternatively, the unit dosage form of the invention can be a monolayerfilm that is an dopamine agonist-containing acidic layer which is coatedwith or impregnated with a particulate base. The particulate base can beincorporated into the monolayer film using the methods described in PCTPublication No. WO/2009/052421, U.S. Patent Publication No. 20060210610,each of which is incorporated herein by reference. The film of theinvention can include an effervescent particulate (i.e., a particulatecarbonate base) or disintegrant (e.g., materials that favordisintegration or fast dissolution by virtue of their solubility inwater, such as hydrolyzed starches, sugars, and glycerin, which may playa dual role as a plasticizer and disintegrant). Such effervescent filmscan be prepared as described in U.S. Patent Publication No. 20010006677,incorporated herein by reference.

The polymers used in the films of the invention can be polymers thataffect the rate of hydration or mucosal adhesion properties of anadhesive layer. Such polymers can be, for example,carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC, such as Pharmacoat 606™, Shin-Etsu Chemical CompanyLtd., Japan), hydroxyethyl cellulose (HEC, commercially available fromHercules Incorporated, Aqualon Division under the tradename NATROSOL™),and methyl cellulose, optionally in a mixture with other polymers, suchas polyoxyethylene/polyoxypropylene polymers, copolymers or blockcopolymers, polyvinylpyrrolidone polymers or derivatives, and/or gums.The average molecular weight of the polymer can be selected based on theswelling and dissolution profile sought.

The films of the invention can include blends of one or more lowmolecular weight polymers (e. g., those from about 5 KDa to about 50KDa) and high molecular weight polymers (e. g., those from about 60 KDato about 500 KDa) in order to achieve desirable properties ofdissolution and mechanical strength. For example, a combination ofhydroxypropyl cellulose (e. g., Klucel, grade JF, Hercules Inc., AqualonDivision) and hydroxypropyl methylcellulose (e. g., Methocel, grades E5,E50, E4M, and SG A16M by Dow Chemical) can be used. These water solublecellulose derivative polymers have molecular weights of about 140,000;30,000; 90,000; 400,000; and greater than about 100,000 daltons,respectively. The molecular weights of the water soluble polymers can bedetermined as described in Keary, Carbohydrate Polymers 45:293 (2001),which is incorporated herein by reference.

Mixtures of less soluble and/or less swellable polymers with moresoluble or more swellable polymers can help transition the film to asufficiently dissolved form. For example, the film can include carbamer,polyethylene oxide, ethylcellulose, titanium oxide and colorant (such asF, D and C blue lake colorant). Often the film is formed using apharmaceutically appropriate solvent such as ethanol, water, mixtures,or the like. Such solvents are typically largely evaporated away priorto use. Optionally, the films comprise a blend of more than one polymersor more than one molecular weight of a given set of polymers in order tocontrol the rate of hydration, physical properties and mechanicalproperties.

The film of the invention can, optionally, be a multilaminate productincluding a monolayer or bilayer of the invention affixed to anadditional slow-dissolving outer layer. Such a multilaminate film wouldbe placed with this slow-dissolving layer away from the mucosal layer,such that it creates a barrier layer and provides for directionaldelivery of the dopamine agonist to the mucosa, increasing the rate ofuptake.

Basic Layers

The multi-layered films of the invention can include a film formed froma basic polymer. Polyamines which can be used in the unit dosage formsof the invention include homo and copolymers ofdimethylaminoethyl-acrylate, dimethylaminoethyl-methacrylate,dimethylaminopropyl-acrylate, dimethylaminpropyl-methacrylate, or othersimilar amino-functionalized acrylate, chitosan or partially hydrolyzedchitin in a substantially basic form, homo and co polymers ofpolyethyleimine, polylysine, polyvinylimidazole, or polyvinylamine. Incertain embodiments the polyamine is Eudragit E100.

Other Components

Plasticizers, penetration enhancers, flavoring agents, preservatives,odorants, coloring agents, and the like can be included in the unitdosage forms of the invention.

Plasticizers will generally modify the feel, softness, flexibility (inan un-wetted state) of the unit dosage forms of the invention.Penetration enhancers may, in some cases, act as plasticizers. Examplesof plasticizers include, without limitation, glycerol, propylene glycol,fatty acid esters, such as glyceryl oleate, polyalcohols, sorbitanesters, citric acid esters, polyethylene glycol (e.g., PEG 400),polyvinyl alcohol, polyvinyl methyl ether, triacetin; mannitol, xylitol,and sorbitol. The plasticizer can be present in any suitable range,including, for example about 0.5% to 30%, 10% to 20%, or 15% to 18% byweight of the dry film.

Permeation enhancers can be used to improve the permeability of thedopamine agonist at the mucosal membrane in the unit dosage forms of theinvention. One or more permeation enhancers maybe used to modulate therate of mucosal absorption of the dopamine agonist. Any effectivepermeation enhancers may be used including, for example, ionicsurfactants, nonionic surfactants, bile salts, such as sodium cholate,sodium glycocholate, sodium glycodeoxycholate, taurodeoxycholate, sodiumdeoxycholate, sodium lithocholate chenocholate, chenodeoxycholate,ursocholate, ursodeoxy-cholate, hyodeoxycholate, dehydrocholate,glycochenocholate, taurochenocholate, and taurochenodeoxycholate; sodiumdodecyl sulfate (SDS), dimethyl sulfoxide (DMSO), N-lauroyl sacrcosine,sorbitan monolaurate, stearyl methacrylate,N-dodecylazacycloheptan-2-one, N-dodecyl-2-pyrrolidinone,N-dodecyl-2-piperidinone, 2-(1-nonyl)-1,3-dioxolane, N-(2-methoxymethyl)dodecylamine, N-dodecylethanolamine,N-dodecyl-N-(2-methoxymethyl)acetamide,1-N-dodecyl-2-pyrrolidone-5-carboxylic acid,2-pentyl-2-oxo-pyrrolidineacetic acid,2-dodecyl-2-oxo-1-pyrrolidineacetic acid,2-dodecyl-2-oxo-1-pyrrolidineacetic acid,1-azacylioheptan-2-one-dodecylacetic acid, menthol, propylene glycol,glycerol monostearate, sorbitol monolaurate, glycerol dilaurate,tocopherol acetate, phosphatidyl choline, glycerol, polyethyleneglycol,monoglycerides, such as glycerol monostearate, glycerol monolaurate,glycerol caprylate, diglycerides, triglycerides, and succinylateddiglycerides and monoglycerides, such as glycerol succinyl caprylatelecithin, tween surfactants, sorbitan surfactants, sodium laurylsulfate; salts, acids and other derivatives of saturated and unsaturatedfatty acids, fatty alcohols, surfactants, bile salt analogs, derivativesof bile salts, or such synthetic permeation enhancers as described inU.S. Pat. No. 4,746,508, which is incorporated herein by reference.

A sweetener, flavoring agent and/or odorant can be added to the unitdosage forms of the invention to make them more palatable. At least oneflavoring agent or odorant composition may be used. Any effective flavoror odor may be rendered. The flavoring agents may be natural,artificial, or a mixture thereof. The flavoring agent gives a flavorthat is will help to reduce the undesirable taste of the activeingredient. In one embodiment, the flavoring agent may give the flavorof mint, menthol, honey lemon, orange, lemon lime, grape, cranberry,vanilla berry, bubble gum, or cherry. The flavoring agent can be naturalor artificial sweetener, such as sucrose, Magnasweet™, sucralose,xylitol, sodium saccharin, cyclamate, aspartame, acesulfame, and saltsthereof.

Apomorphine is susceptible to oxidative degradation. To minimizeoxidative degradation it is desirable that the formulations of theinvention contain one or more antioxidants. Antioxidants that can beused in the films of the invention can be selected from thiols (e.g.,aurothioglucose, dihydrolipoic acid, propylthiouracil, thioredoxin,glutathione, cysteine, cystine, cystamine, thiodipropionic acid),sulphoximines (e.g., buthionine-sulphoximines,homo-cysteine-sulphoximine, buthionine-sulphones, and penta-, hexa- andheptathionine-sulphoximine), metal chelators (e.g, α-hydroxy-fattyacids, palmitic acid, phytic acid, lactoferrin, citric acid, lacticacid, and succinic acid, malic acid, humic acid, bile acid, bileextracts, bilirubin, biliverdin, EDTA, EGTA, and DTPA and saltsthereof), sodium metabisulfite, sodium thiosulfate, vitamins and vitaminderivatives (e.g., vitamin E, vitamin C, ascorbyl palmitate, Mg ascorbylphosphate, and ascorbyl acetate), phenols (e.g., butylhydroxytoluene,butylhydroxyanisole, ubiquinol, nordihydroguaiaretic acid,trihydroxybutyrophenone), benzoates (e.g., coniferyl benzoate), uricacid, mannose, propyl gallate, selenium (e.g., selenium-methionine),stilbenes (e.g., stilbene oxide and trans-stilbene oxide), andcombinations thereof. The total amount of antioxidant included in thefilms can be from 0.001% to 3% by weight, preferably 0.01% to 1% byweight, in particular 0.05% to 0.5% by weight, based on the total weightof the formulation. Other dopamine agonists may also benefit from theinclusion of antioxidants in the formulations of the invention.

The films of the invention can include from 1 to 50% (ww) of one or morehydrolyzed starches. Various hydrolyzed starches may be utilizedincluding maltrodextrins with a DE greater than 10 and dried glucosesyrups which have a DE above 20. Suitable hydrolyzed starch products arecommercially available from Grain Processing Corporation of Muscatine,Iowa under trademarks such as MALTRIN M200®, MALTRIN 180®, and MALTRIN250®. MALTRIN M200® is a hydrolyzed starch product having a DE of 20,and MALTRIN 180® is a hydrolyzed starch product having a DE of 18.Dextrose equivalent (DE) is the relative sweetness of sugars,oligosaccharides, or blends compared to dextrose, both expressed as apercentage. For example, a maltodextrin with a DE of 10 would be 10% assweet as dextrose (DE=100), while sucrose, with a DE of 120, would be1.2 times as sweet as dextrose. For solutions made from starch, it is anestimate of the percentage reducing sugars present in the total starchproduct. The DE describes the degree of conversion of starch todextrose: starch is close to 0, glucose/dextrose is 100 (percent),dextrins vary between 1 and 13, and maltodextrins vary between 3 and 20.The DE gives an indication of the average degree of polymerisation (DP)for starch sugars. The rule of thumb isDE×DP=120.

In certain embodiments, the various components (e.g., plasticizers,penetration enhancers, flavoring agents, preservatives, odorants,coloring agents, particulate base, and dopamine agonist particles)included in the unit dosage forms of the invention can be combined andincorporated into a first portion that is acidic and includes thedopamine agonist, or combined and incorporated into a second portionthat includes a pH neutralizing component, or the components may bedivided between the two portions. In some instances it may be desirableto minimize interaction between the acidic portion of the unit dosageform and the basic portion of the unit dosage form by including abarrier between the two. For example, a barrier can be included in theunit dosage forms of the invention as a third layer interposed betweenthe acidic layer and the basic layer of a multilayer sublingual dosageform. Alternatively, the barrier can be a rapidly dissolving coating onthe surface of a particulate component in the unit dosage form, such asa coated particulate base coated onto, or embedded within, an acidicportion of the unit dosage form. In still another approach, the barriercan be a rapidly dissolving coating on the surface of dopamine agonistparticles in the unit dosage form, which further includes a basicportion. These approaches can be utilized to ensure that the dopamineagonist-containing acidic portion of the unit dosage form is notneutralized prior to the administration to a subject.

Dopamine Agonist Particles

The pharmaceutical formulations described herein can include dopamineagonist particles having an effective particle size of from about 1micron to about 10 microns. The starting dopamine agonist compositioncan be predominantly crystalline, predominantly amorphous, or a mixturethereof, and can include unmodified dopamine agonist.

In an alternative approach, the pharmaceutical formulations describedherein can include dopamine agonist particles having an effectiveparticle size of less than about 1 micron (i.e., nanoparticulateformulations). The starting dopamine agonist composition can bepredominantly crystalline, predominantly amorphous, or a mixturethereof, and can include unmodified dopamine agonist.

These dopamine agonist particles can be made by using any method knownin the art for achieving the desired particle sizes. Useful methodsinclude, for example, milling, homogenization, supercritical fluidfracture, or precipitation techniques. Exemplary methods are describedin U.S. Pat. Nos. 4,540,602; 5,145,684; 5,518,187; 5,718,388; 5,862,999;5,665,331; 5,662,883; 5,560,932; 5,543,133; 5,534,270; and 5,510,118;5,470,583, each of which is specifically incorporated by reference.

Milling to Obtain Submicron Dopamine Agonist Particles

In one approach, the dopamine agonist, or a salt thereof, is milled inorder to obtain micron or submicron particles. The milling process canbe a dry process, e.g., a dry roller milling process, or a wet process,i.e., wet-grinding. A wet-grinding process is described in U.S. Pat.Nos. 4,540,602, 5,145,684, 6,976,647 and EPO 498,482, the disclosures ofwhich are hereby incorporated by reference. Thus, the wet grindingprocess can be practiced in conjunction with a liquid dispersion mediumand dispersing or wetting agents such as described in thesepublications. Useful liquid dispersion media include safflower oil,ethanol, n-butanol, hexane, or glycol, among other liquids selected fromknown organic pharmaceutical excipients (see U.S. Pat. Nos. 4,540,602and 5,145,684), and can be present in an amount of 2.0-70%, 3-50%, or5-25% by weight based on the total weight of the dopamine agonist in theformulation.

The grinding media for the particle size reduction step can be selectedfrom rigid media, typically spherical in shape, though non-sphericalgrinding media could also be used. The grinding media preferably canhave a mean particle size from 1 mm to about 500 microns. For finegrinding, the grinding media particles can have a mean particle sizefrom about 0.05 to about 0.6 mm. Smaller size grinding media will resultin smaller size dopamine agonist particles as compared to the sameconditions using larger sized grinding media. In selecting material,grinding media with higher density, e.g., glass (2.6 g/cm³), zirconiumsilicate (3.7 g/cm³), and zirconium oxide (5.4 g/cm³) and 95% zirconiumoxide stabilized with yttrium, can be utilized for more efficientmilling. Alternatively, polymeric grinding media can be used. Polymericresins suitable for use herein are chemically and physically inert,substantially free of metals, solvent and monomers, and of sufficienthardness and friability to enable them to avoid being chipped or crushedduring grinding. Suitable polymeric resins include, without limitation,crosslinked polystyrenes, such as polystyrene crosslinked withdivinylbenzene, styrene copolymers, polycarbonates, polyacetals, such asDelrin™, vinyl chloride polymers and copolymers, polyurethanes,polyamides, poly(tetrafluoroethylenes), e.g., Teflon™, and otherfluoropolymers, high density polyethylenes, polypropylenes, celluloseethers and esters such as cellulose acetate, polyhydroxymethacrylate,polyhydroxyethyl acrylate, and silicone containing polymers such aspolysiloxanes.

Grinding can take place in any suitable grinding mill. Suitable millsinclude an airjet mill, a roller mill, a ball mill, an attritor mill, avibratory mill, a planetary mill, a sand mill and a bead mill. A highenergy media mill is preferred when small particles are desired. Themill can contain a rotating shaft.

The preferred proportions of the grinding media, dopamine agonist, theoptional liquid dispersion medium, and dispersing, wetting or otherparticle stabilizing agents present in the grinding vessel can varywithin wide limits and depend on, for example, the size and density ofthe grinding media, the type of mill selected, the time of milling, etc.The process can be carried out in a continuous, batch or semi-batchmode. In high energy media mills, it can be desirable to fill 80-95% ofthe volume of the grinding chamber with grinding media. On the otherhand, in roller mills, it frequently is desirable to leave the grindingvessel up to half filled with air, the remaining volume comprising thegrinding media and the liquid dispersion media, if present. This permitsa cascading effect within the vessel on the rollers which permitsefficient grinding. However, when foaming is a problem during wetgrinding, the vessel can be completely filled with the liquid dispersionmedium or an anti-foaming agent may be added to the liquid dispersion.

The attrition time can vary widely and depends primarily upon themechanical means and residence conditions selected, the initial anddesired final particle size, among other factors. For roller mills,processing times from several days to weeks may be required. On theother hand, milling residence times of less than about 2 hours aregenerally required using high energy media mills. After attrition iscompleted, the grinding media is separated from the milled dopamineagonist particulate product (in either a dry or liquid dispersion form)using conventional separation techniques, such as by filtration, orsieving through a mesh screen.

To produce dopamine agonist particles having an effective particle sizeof less than about 1 micron, the grinding media can be made from beadshaving a size ranging from 0.05 mm to 4 mm. For example, high energymilling of dopamine agonist with yttrium stabilized zirconium oxide 0.4mm beads for a milling residence time of 25 minutes to 1.5 hours inrecirculation mode at 1200 to 3000 RPM. In another approach, high energymilling of dopamine agonist with 0.1 mm zirconium oxide balls for amilling residence time of 2 hours in batch mode can be used. The millingconcentration can be from about 10% to about 30% dopamine agonist byweight in comparison to the milling slurry weight, which can contain awetting and/or dispersing agent to coat the initial suspension so auniform feed rate may be applied in continuous milling mode.Alternatively, batch milling mode is utilized with a milling mediacontaining an agent to adjust viscosity and/or provide a wetting effectso that the dopamine agonist is well dispersed amongst the grindingmedia.

Microprecipitation to Obtain Dopamine Agonist Nanoparticles

Dopamine agonist particles can also be prepared by homogeneousnucleation and precipitation in the presence of a wetting agent ordispersing agent using methods analogous to those described in U.S. Pat.Nos. 5,560,932 and 5,665,331, which are specifically incorporated byreference. Such a method can include the steps of: (1) dispersing thedopamine agonist in a suitable liquid media; (2) adding the mixture fromstep (1) to a mixture including at least one dispersing agent or wettingagent such that at the appropriate temperature, the dopamine agonist isdissolved; and (3) precipitating the formulation from step (2) using anappropriate anti-solvent. The method can be followed by removal of anyformed salt, if present, by dialysis or filtration and concentration ofthe dispersion by conventional means. In one embodiment, the dopamineagonist particles are present in an essentially pure form and dispersedin a suitable liquid dispersion media. In this approach the dopamineagonist particles are a discrete phase within the resulting mixture.Useful dispersing agents, wetting agents, solvents, and anti-solventscan be experimentally determined.

Homogenization to Obtain Dopamine Agonist Nanoparticles

Dopamine agonist particles can also be prepared by high pressurehomogenization (see U.S. Pat. No. 5,510,118). In this approach dopamineagonist particles are dispersed in a liquid dispersion medium andsubjected to repeated homogenization to reduce the particle size of thedopamine agonist particles to the desired effective average particlesize. The dopamine agonist particles can be reduced in size in thepresence of at least one or more dispersing agents or wetting agents.Alternatively, the dopamine agonist particles can be contacted with oneor more dispersing agents or wetting agents either before or afterattrition. Other materials, such as a diluent, can be added to thedopamine agonist/dispersing agent mixture before, during, or after thesize reduction process. For example, unprocessed dopamine agonist can beadded to a liquid medium in which it is essentially insoluble to form apremix (i.e., about 0.1-60% w/w dopamine agonist and about 20-60% w/wdispersing agents or wetting agents). The apparent viscosity of thepremix suspension is preferably less than about 1000 centipoise. Thepremix can then be transferred to a microfluidizer and circulatedcontinuously first at low pressures, and then at maximum capacity (i.e.,3,000 to 30,000 psi) until the desired particle size reduction isachieved. The resulting dispersion of dopamine agonist particles can bespray coated onto a sublingual pharmaceutical formulation of theinvention using techniques well known in the art.

Milling with Simethicone

Foaming during the nanosizing can present formulation issues and canhave negative consequences for particle size reduction. For example,high levels of foam or air bubbles in the mill can cause a drasticincrease in viscosity rendering the milling process inoperable. Even avery low level of air presence can dramatically reduce millingefficiency causing the desired particle size unachievable. This may bedue to the resultant air in the mill cushioning the milling balls andlimiting grinding efficiency. The air also can form a microemulsion withthe milled ingredients which presents many issues with respect to thedelivery of an accurate dose and palatability. Addition of a smallamount of simethicone is a very effective anti-foaming agent whichminimizes milling variability or special handling techniques to avoidthe introduction of air into the milling process.

The Use of Wetting and Dispersing Agents

The dopamine agonist particles can be prepared with the use of one ormore wetting and/or dispersing agents, which are, e.g., adsorbed on thesurface of the dopamine agonist particle. The dopamine agonist particlescan be contacted with wetting and/or dispersing agents either before,during or after size reduction. Generally, wetting and/or dispersingagents fall into two categories: non-ionic agents and ionic agents. Themost common non-ionic agents are excipients which are contained inclasses known as binders, fillers, surfactants and wetting agents.Limited examples of non-ionic surface stabilizers arehydroxypropylmethylcellulose, polyvinylpyrrolidone, Plasdone, polyvinylalcohol, Pluronics, Tweens and polyethylene glycols (PEGs). Ionic agentsare typically organic molecules bearing an ionic bond such that themolecule is charged in the formulation, such as long chain sulfonic acidsalts (e.g., sodium lauryl sulfate and dioctyl sodium sulfosuccinate).

Excipients, such as wetting and dispersing agents, can be applied to thesurface of the dopamine agonist nanoparticulate via spray drying, spraygranulation, or spray layering process. These procedures are well knownin those skilled in the art. It is also common to add additionalexcipients prior to removal of solvent in the nanoparticulate suspensionto aid in the dispersion of the solid composition in medium in which thesolid composition will be exposed (e.g. saliva) to further preventagglomeration and/or particle size growth of the small dopamine agonistparticles. An example of such an additional excipient is a redispersingagent. Suitable redispersing agents include, without limitation, sugars,polyethylene glycols, urea and quaternary ammonium salts.

Therapy

Representative examples of diseases and conditions treatable using thesublingual formulations of the invention are as listed hereinabove, andinclude, but are not limited to, Parkinson's disease, sexualdysfunction, and depressive disorders, such as major depression andbipolar disorder.

Sublingual formulations of the invention include rapidly disintegratingor dissolving dosage forms, also known as fast dissolve, fast or rapidmelt, and quick disintegrating dosage forms. These dosage forms dissolveor disintegrate rapidly in the patient's mouth without chewing or theneed for water within a short time frame. Because of their ease ofadministration, such compositions are particularly useful for thespecific needs of patients with compromised motor skills. The sublingualformulations may be in unit dosage form in the shape of, for example, alozenge, a pill, a tablet, a film, or a strip. Alternatively, thesublingual formulations may be prepared in non-unit dosage forms, suchas a gel.

The dopamine agonist may be administered in its free base form or as apharmaceutically acceptable salt, such as a non-toxic acid additionsalts or metal complexes that are commonly used in the pharmaceuticalindustry. Examples of acid addition salts include organic acids such asacetic, glucuronic, citric, lactic, pamoic, maleic, citric, malic,maleic, ascorbic, succinic, benzoic, palmitic, suberic, salicylic,tartaric, methanesulfonic, toluenesulfonic, or trifluoroacetic acids orthe like; polymeric acids such as tannic acid, carboxymethyl cellulose,alginic acid, polyacrylate, and copolymers of acrylate, methacrylate,and/or carboxymethyl polymer derivatives; and inorganic acid such ashydrochloric acid, hydrobromic acid, sulfuric acid phosphoric acid, orthe like. Metal complexes include calcium, zinc, iron, and the like. Incertain instances the formulation of the invention includes thehydrochloride salt of a dopamine agonist.

The formulations can be administered to patients in therapeuticallyeffective amounts. For example, an amount is administered whichprevents, reduces, or eliminates the symptoms of Parkinson's disease,sexual dysfunction, or depression, respectively. Typical dose ranges arefrom about 0.5 mg to about 30 mg of apomorphine, or a salt thereof,given up to five times per day. Typical dose ranges are from about 0.2mg to about 20 mg of bromocriptine, or a salt thereof, given up to fivetimes per day. Typical dose ranges are from about 0.2 mg to about 20 mgof cabergoline, or a salt thereof, given up to five times per day.Typical dose ranges are from about 0.3 mg to about 30 mg ofdihydroergocryptine, or a salt thereof, given up to five times per day.Typical dose ranges are from about 0.05 mg to about 10 mg of lisuride,or a salt thereof, given up to five times per day. Typical dose rangesare from about 0.5 mg to about 75 mg of piribedil, or a salt thereof,given up to five times per day. Typical dose ranges are from about 0.05mg to about 10 mg of pergolide, or a salt thereof, given up to fivetimes per day. Typical dose ranges are from about 0.1 mg to about 20 mgof pramipexole, or a salt thereof, given up to five times per day.Typical dose ranges are from about 0.1 mg to about 20 mg of rotigotine,or a salt thereof, given up to five times per day. Typical dose rangesare from about 0.1 mg to about 40 mg of rotigotine, or a salt thereof,given up to five times per day. The exemplary dosage of dopamine agonistto be administered is likely to depend on such variables as the type andextent of the condition, the overall health status of the particularpatient, the particular dopamine agonist being administered, and theparticular sublingual formulation being used.

Potential adverse effects can be ameliorated by administeringapomorphine, or an apomorphine prodrug, in combination with ananti-emetic agent, such as nicotine, lobeline sulfate, pipamazine,oxypendyl hydrochloride, ondansetron, buclizine hydrochloride, cyclizinehydrochloride, dimenhydrinate, scopolamine, metopimazine, benzauinaminehydrochloride or diphenidol hydrochloride. In certain instances it maybe desirable to incorporate the anti-emetic into the sublingualformulation for simultaneous administration in combination withapomorphine, or apomorphine prodrug.

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how themethods and compounds claimed herein are performed, made, and evaluated,and are intended to be purely exemplary of the invention and are notintended to limit the scope of what the inventors regard as theirinvention.

Example 1 Monolayer and Bilayer Films

Films A-H, J, K, and L were prepared as described below. Films A-H wereprepared using a solid particulate apomorphine hydrochloride having aneffective particle size in the range of 125 μm to 250 μm. Films J, K,and L were prepared using a solid particulate apomorphine hydrochloridethat was processed to produce an effective particle size of about 8 μm.For Films J, K, and L apomorphine hydrochloride was milled using aJet-Pulverizer 2 Micron-Master cyclone discharge mill with stainlesssteel liner. Nitrogen was used as the process gas at a pressure of 100PSI and temperature of 25-45° C. The apomorphine hydrochloride was fedinto the mill using a “V” groove vibratory feeder and recovered in anintegrated bottom collector to reduce material loss associated with adust bag collector. The design of this milling unit is described in U.S.Pat. No. 3,559,895.

Film A.

Film A is a monolayer film containing the components and amounts listedin Table A. Film A was prepared by first mixing sodium metabisulfite,disodium EDTA, propylene glycol, maltodextrin, and sucralose with water,and stirring the mixture. Acetone and menthol were added to thissolution, and the mixture stirred. Apomorphine hydrochloride was added,with stirring, forming a clear solution. Hypromellose was added slowlywith stirring until a uniform, clear, viscous liquid was produced. Theresulting mixture was placed under vacuum to eliminate air bubbles, castas a uniform layer onto an inert support, and dried in an oven. Theresulting dried film was clear in appearance.

TABLE A bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 39.8794 — — acetone 39.8247 — — sodium 0.1693 0.8342 0.5422metabisulfite disodium EDTA 0.1693 0.8342 0.5422 apomorphine HCl 4.684523.0810 15.0027 menthol 1.1400 5.6169 3.6510 propylene glycol 2.289911.2826 7.3337 maltodextrin M180 3.6340 17.9051 11.6383 sucralose 0.55262.7227 1.7698 Methocel E50 4.3210 21.2900 13.8385 Methocel E5 3.335316.4334 10.6817 Total mass, mg 100.0000 100.0000 65.0000

Film B.

Film B is a monolayer film containing the components and amounts listedin Table B. Film B was prepared by first mixing sodium metabisulfite,disodium EDTA, glycerin, maltodextrin, and sucralose with water, andstirring the mixture. Acetone and menthol were added to this solution,and the mixture stirred. Apomorphine hydrochloride was added andstirred, forming an opaque dispersion. Hypromellose was added slowlywith stirring until a uniform, opaque, viscous liquid was produced. Theresulting mixture was placed under vacuum to eliminate air bubbles, castas a uniform layer onto an inert support, and dried in an oven. Theresulting dried film was opaque white in color.

TABLE B bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 33.3333 — — acetone 33.3333 — — sodium 0.3280 0.9841 0.2460metabisulfite disodium EDTA 0.3377 1.0130 0.2533 apomorphine HCl 20.000060.0000 15.0000 menthol 3.0565 9.1694 2.2924 glycerin 1.7945 5.38351.3459 Maltrin M180 0.8548 2.5644 0.6411 sucralose 1.0613 3.1838 0.7959Methocel E50 2.2696 6.8087 1.7022 Methocel E5 3.6310 10.8931 2.7233Total mass, mg 100.0000 100.0000 25.0000 Theoretical solids, 33.3334 — —%

Film C.

Film C is a bilayer film formed from an apomorphine layer containing thecomponents and amounts listed in Table C1 and a neutralizing layercontaining the components and amounts listed in Table C2.

Apomorphine layer C1 was prepared by first mixing sodium metabisulfite,disodium EDTA, glycerin, maltodextrin, and sucralose with water, andstirring the mixture. Acetone and menthol were added to this solution,and the mixture stirred. Apomorphine hydrochloride was added andstirred, forming an opaque dispersion. Hypromellose was added slowlywith stirring until a uniform, opaque, viscous liquid was produced. Theresulting mixture was placed under vacuum to eliminate air bubbles, castas a uniform layer onto an inert support, and dried in an oven. Theresulting dried film was opaque white in color.

TABLE C1 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 33.3333 — — acetone 33.3333 — — sodium 0.3280 0.9841 0.2460metabisulfite disodium EDTA 0.3377 1.0130 0.2533 apomorphine HCl 20.000060.0000 15.0000 menthol 3.0565 9.1694 2.2924 glycerin 1.7945 5.38351.3459 Maltrin M180 0.8548 2.5644 0.6411 sucralose 1.0613 3.1838 0.7959Methocel E50 2.2696 6.8087 1.7022 Methocel E5 3.6310 10.8931 2.7233Total mass, mg 100.0000 100.0000 25.0000 Theoretical solids, 33.3334 — —%

Neutralizing layer C2 was prepared by slowly adding sodium carboxymethylcellulose to water with stirring until a uniform, clear, viscous liquidis produced. Sodium phosphate tribasic, sodium phosphate dibasic, sodiummetabisulfite, disodium EDTA, glycerin, and maltodextrin were then alladded, and the mixture was stirred. Acetone was added to this solution,and the mixture was stirred, until a uniform, clear, viscous liquid wasproduced. The resulting mixture was placed under vacuum to eliminate airbubbles, cast as a uniform layer onto an inert support, and dried in anoven. The resulting dried layer was clear in appearance.

TABLE C2 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 70.0000 — — acetone 10.0000 — — sodium phosphate tribasic 3.348016.7400 1.6740 (Na₃PO₄) disodium phosphate dibasic 0.5580 2.7900 0.2790(Na₂HPO₄) sodium metabisulfite 0.2158 1.0792 0.1079 disodium EDTA 0.18350.9174 0.0917 glycerin 1.9256 9.6280 0.9628 Maltrin M180 5.2000 26.00002.6000 sodium CMC, 7L2P 8.5691 42.8454 4.2845 Total mass, mg 100.0000100.0000 10.0000 Theoretical solids, % 20.0000 — —

The apomorphine layer and neutralizing layer were laminated together byapplying a spray of ethanol between them. This bilayer construction,sandwiched between two inert supports, was dried in an oven. The driedbilayer was removed from the inert supports, cut into unit-dose films ofa predetermined size (22 mm×22 mm), and packaged into individual foilpouches. The resulting dried bilayer film was opaque white in color.

Film D.

Film D is a bilayer film formed from an apomorphine layer containing thecomponents and amounts listed in Table D1 and a neutralizing layercontaining the components and amounts listed in Table D2.

Apomorphine layer D1 was prepared by slowly adding hydroxyethylcellulose and hypromellose to water with stirring until a uniform,clear, viscous liquid was produced. Sodium metabisulfite, disodium EDTA,glycerin, maltodextrin, and sucralose were then all added, and themixture stirred. Acetone and menthol were then added to this solution,and the mixture stirred. Apomorphine hydrochloride was then added andthe mixture stirred, forming an opaque dispersion. The resulting mixturewas placed under vacuum to eliminate air bubbles, cast as a uniformlayer onto an inert support, and dried in an oven. The resulting driedlayer was opaque white in color.

TABLE D1 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 38.6792 — — acetone 14.1509 — — sodium 0.4688 0.9939 0.4290metabisulfite disodium EDTA 0.4643 0.9843 0.4249 apomorphine HCl 16.391234.7494 15.0000 menthol 2.5050 5.3105 2.2924 glycerin 4.3386 9.19783.9703 Maltrin M180 19.2072 40.7194 17.5770 sucralose 0.8698 1.84390.7959 Natrosol 250 G 1.2332 2.6145 1.1286 Natrosol 250 L 1.2332 2.61451.1286 Methocel E5 0.4584 0.9718 0.4195 Total mass, mg 100.0000 100.000043.1662 Theoretical solids, 47.1698 — — %

Neutralizing layer D2 was prepared by slowly adding hydroxyethylcellulose to water with stirring until a uniform, clear, viscous liquidwas produced. Sodium phosphate tribasic, sodium phosphate dibasic,sodium metabisulfite, disodium EDTA, glycerin, and maltodextrin werethen all added, and the mixture stirred. Acetone was added to thissolution, and the mixture stirred, until a uniform, clear, viscousliquid was produced. The resulting mixture was placed under vacuum toeliminate air bubbles, cast as a uniform layer onto an inert support,and dried in an oven. The resulting dried layer was clear in appearance.

TABLE D2 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 79.6754 — — acetone 5.8157 — — sodium phosphate tribasic 2.433916.7751 1.6775 (Na₃PO₄) disodium phosphate dibasic 0.4056 2.7959 0.2796(Na₂HPO₄) sodium metabisulfite 0.1255 0.8652 0.0865 disodium EDTA 0.10670.7355 0.0735 glycerin 1.1199 7.7186 0.7719 Maltrin M180 5.2342 36.07563.6076 Natrosol 250 G 3.3887 23.3562 2.3356 Natrosol 250 L 1.694411.6781 1.1678 Total mass, mg 100.0000 100.0000 10.0000 Theoreticalsolids, % 20.2179 — —

The apomorphine layer and neutralizing layer were laminated together byapplying a spray of ethanol between them. This bilayer construction,sandwiched between two inert supports, was dried in an oven. The driedbilayer was removed from the inert supports, cut into unit-dose films ofa predetermined size (22 mm×22 mm), and packaged into individual foilpouches. The resulting dried bilayer film was opaque white in color.

Film E.

Film E is a bilayer film formed from an apomorphine layer containing thecomponents and amounts listed in Table E1 and a neutralizing layercontaining the components and amounts listed in Table E2.

Apomorphine layer E1 was prepared by slowly adding hydroxyethylcellulose and hypromellose to water with stirring until a uniform,clear, viscous liquid was produced. Sodium metabisulfite, disodium EDTA,glycerin, maltodextrin, and sucralose were then all added, and themixture was stirred. Acetone and menthol were added to this solution,and the mixture was stirred. Apomorphine hydrochloride was then addedwith stirring, forming an opaque dispersion. The resulting mixture wasplaced under vacuum to eliminate air bubbles, cast as a uniform layeronto an inert support, and dried in an oven. The resulting dried layerwas opaque white in color.

TABLE E1 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 38.6792 — — acetone 14.1509 — — sodium 0.4688 0.9939 0.4290metabisulfite disodium EDTA 0.4643 0.9843 0.4249 apomorphine HCl 16.391234.7494 15.0000 menthol 2.5050 5.3105 2.2924 glycerin 4.3386 9.19783.9703 Maltrin M180 19.2072 40.7194 17.5770 sucralose 0.8698 1.84390.7959 Natrosol 250 G 1.2332 2.6145 1.1286 Natrosol 250 L 1.2332 2.61451.1286 Methocel E5 0.4584 0.9718 0.4195 Total mass, mg 100.0000 100.000043.1662 Theoretical solids, 47.1698 — — %

Neutralizing layer E2 was prepared by slowly adding hydroxyethylcellulose to water with stirring until a uniform, clear, viscous liquidwas produced. Meglumine, sodium metabisulfite, disodium EDTA, glycerin,and maltodextrin were then all added, and the mixture stirred. Acetonewas added to this solution, and the mixture stirred, until a uniform,clear, viscous liquid was produced. The resulting mixture was placedunder vacuum to eliminate air bubbles, cast as a uniform layer onto aninert support, and dried in an oven. The resulting dried layer was clearin appearance.

TABLE E2 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 85.8172 — — acetone 1.7129 — — meglumine 5.1388 41.2092 10.3023sodium 0.0370 0.2965 0.0741 metabisulfite disodium EDTA 0.0314 0.25200.0630 glycerin 1.0963 8.7913 2.1978 Maltrin M180 0.6852 5.4946 1.3736Natrosol 250 G 2.7407 21.9782 5.4946 Natrosol 250 L 2.7407 21.97825.4946 Total mass, mg 100.0000 100.0000 25.0000 Theoretical solids,12.4699 — — %

The apomorphine layer and neutralizing layer were laminated together byapplying a spray of ethanol between them. This bilayer construction,sandwiched between two inert supports, was dried in an oven. The driedbilayer was removed from the inert supports, cut into unit-dose films ofa predetermined size (22 mm×22 mm), and packaged into individual foilpouches. The resulting dried bilayer film was opaque white in color.

Film F.

Film F is a bilayer film formed from an apomorphine layer containing thecomponents and amounts listed in Table F1 and a neutralizing layercontaining the components and amounts listed in Table F2.

Apomorphine layer F1 was prepared by slowly adding hydroxyethylcellulose and hypromellose to water with stirring until a uniform,clear, viscous liquid was produced. Sodium metabisulfite, disodium EDTA,glycerin, maltodextrin, and sucralose were then all added, and themixture was stirred. Acetone and menthol were added to this solution,and the mixture stirred. Apomorphine hydrochloride was added withstirring, forming an opaque dispersion. The resulting mixture was placedunder vacuum to eliminate air bubbles, cast as a uniform layer onto aninert support, and dried in an oven. The resulting dried layer wasopaque white in color.

TABLE F1 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 55.2012 — — acetone 6.8337 — — sodium 0.3984 1.0495 0.2860metabisulfite disodium EDTA 0.3984 1.0495 0.2860 apomorphine HCl 20.895655.0389 15.0000 menthol 2.6361 6.9436 1.8924 glycerin 2.7861 7.33852.0000 Maltrin M180 3.4423 9.0671 2.4711 sucralose 0.8302 2.1867 0.5959Natrosol 250 L 6.1328 16.1539 4.4025 Methocel E5 0.4451 1.1723 0.3195Total mass, mg 100.0000 100.0000 27.2534 Theoretical solids, 37.9651 — —%

Neutralizing layer F2 was prepared by slowly adding hydroxyethylcellulose to water slowly with stirring until a uniform, clear, viscousliquid was produced. Meglumine, sodium metabisulfite, disodium EDTA,glycerin, and maltodextrin were then all added, and the mixture wasstirred. Acetone was added to this solution, and the mixture stirred,until a uniform, clear, viscous liquid was produced. The resultingmixture was placed under vacuum to eliminate air bubbles, cast as auniform layer onto an inert support, and dried in an oven. The resultingdried layer was clear in appearance.

TABLE F2 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 60.8111 — — acetone 6.1425 — — meglumine 19.6561 59.4803 9.9630sodium 0.1326 0.4012 0.0672 metabisulfite disodium EDTA 0.1127 0.34100.0571 glycerin 1.4742 4.4610 0.7472 Maltrin M180 4.9140 14.8701 2.4907Natrosol 250 L 6.7568 20.4464 3.4248 Total mass, mg 100.0000 100.000016.7500 Theoretical solids, 33.0464 — — %

The apomorphine layer and neutralizing layer were laminated together byapplying a spray of ethanol between them. This bilayer construction,sandwiched between two inert supports, was dried in an oven. The driedbilayer was removed from the inert supports, cut into unit-dose films ofa predetermined size (22 mm×22 mm), and packaged into individual foilpouches. The resulting dried bilayer film was opaque white in color.

Film G.

Film G is a bilayer film formed from an apomorphine layer containing thecomponents and amounts listed in Table G1 and a neutralizing layercontaining the components and amounts listed in Table G2.

Apomorphine layer G1 was prepared by slowly adding hydroxyethylcellulose and hypromellose to water with stirring until a uniform,clear, viscous liquid was produced. Sodium metabisulfite, disodium EDTA,glycerin, maltodextrin, and sucralose were then all added, and themixture was stirred. Acetone and menthol were added to this solution,and the mixture stirred. Apomorphine hydrochloride was added withstirring, forming an opaque dispersion. The resulting mixture was placedunder vacuum to eliminate air bubbles, cast as a uniform layer onto aninert support, and dried in an oven. The resulting dried layer wasopaque white in color.

TABLE G1 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 55.2012 — — acetone 6.8337 — — sodium 0.3984 1.0495 0.2860metabisulfite disodium EDTA 0.3984 1.0495 0.2860 apomorphine HCl 20.895655.0389 15.0000 menthol 2.6361 6.9436 1.8924 glycerin 2.7861 7.33852.0000 Maltrin M180 3.4423 9.0671 2.4711 sucralose 0.8302 2.1867 0.5959Natrosol 250 L 6.1328 16.1539 4.4025 Methocel E5 0.4451 1.1723 0.3195Total mass, mg 100.0000 100.0000 27.2534 Theoretical solids, 37.9651 — —%

Neutralizing layer G2 was prepared by slowly adding hydroxyethylcellulose to water with stirring until a uniform, clear, viscous liquidwas produced. Sodium citrate, sodium metabisulfite, disodium EDTA,glycerin, and maltodextrin were all added, and the mixture was stirred.Acetone was added to this solution, and the mixture stirred, until auniform, clear, viscous liquid is produced. The resulting mixture wasplaced under vacuum to eliminate air bubbles, cast as a uniform layeronto an inert support, and dried in an oven. The resulting dried layerwas clear in appearance.

TABLE G2 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 68.5434 — — acetone 8.2782 — — sodium citrate 4.9669 21.42915.0358 sodium 0.1787 0.7709 0.1812 metabisulfite disodium EDTA 0.15190.6553 0.1540 glycerin 1.9868 8.5716 2.0143 Maltrin M180 8.2782 35.71528.3931 Natrosol 250 L 7.6159 32.8579 7.7216 Total mass, mg 100.0000100.0000 23.5000 Theoretical solids, 23.1784 — — %

The apomorphine layer and neutralizing layer were laminated together byapplying a spray of ethanol between them. This bilayer construction,sandwiched between two inert supports, was dried in an oven. The driedbilayer was removed from the inert supports, cut into unit-dose films ofa predetermined size (22 mm×22 mm), and packaged into individual foilpouches. The resulting dried bilayer film was opaque white in color.

Film H.

Film H is a bilayer film formed from an apomorphine layer containing thecomponents and amounts listed in Table H1 and a neutralizing layercontaining the components and amounts listed in Table H2.

Apomorphine layer H1 was prepared by slowly adding hydroxyethylcellulose and hypromellose to water with stirring until a uniform,clear, viscous liquid was produced. Sodium metabisulfite, disodium EDTA,glycerin, maltodextrin, and sucralose were then all added, and themixture was stirred. Acetone and menthol were added to this solution,and the mixture stirred. Apomorphine hydrochloride was added withstirring, forming an opaque dispersion. The resulting mixture was placedunder vacuum to eliminate air bubbles, cast as a uniform layer onto aninert support, and dried in an oven. The resulting dried layer wasopaque white in color.

TABLE H1 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 55.2012 — — acetone 6.8337 — — sodium 0.3984 1.0495 0.2860metabisulfite disodium EDTA 0.3984 1.0495 0.2860 apomorphine HCl 20.895655.0389 15.0000 menthol 2.6361 6.9436 1.8924 glycerin 2.7861 7.33852.0000 Maltrin M180 3.4423 9.0671 2.4711 sucralose 0.8302 2.1867 0.5959Natrosol 250 L 6.1328 16.1539 4.4025 Methocel E5 0.4451 1.1723 0.3195Total mass, mg 100.0000 100.0000 27.2534 Theoretical solids, 37.9651 — —%

Neutralizing layer H2 was prepared by slowly adding hydroxyethylcellulose to water with stirring until a uniform, clear, viscous liquidwas produced. Meglumine, sodium citrate, sodium metabisulfite, disodiumEDTA, glycerin, and maltodextrin were then all added, and the mixturestirred. Acetone was added to this solution, and the mixture stirred,until a uniform, clear, viscous liquid was produced. The resultingmixture was placed under vacuum to eliminate air bubbles, cast as auniform layer onto an inert support, and dried in an oven. The resultingdried layer was clear in appearance.

TABLE H2 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 60.2192 — — acetone 6.0828 — — meglumine 14.4769 42.9608 5.0049sodium citrate 5.9611 17.6897 2.0609 sodium metabisulfite 0.1313 0.38960.0454 disodium EDTA 0.1116 0.3312 0.0386 glycerin 1.4599 4.3322 0.5047Maltrin M180 4.8662 14.4406 1.6823 Natrosol 250 L 6.6910 19.8558 2.3132Total mass, mg 100.0000 100.0000 11.6500 Theoretical solids, % 33.6980 ——

The apomorphine layer and neutralizing layer were laminated together byapplying a spray of ethanol between them. This bilayer construction,sandwiched between two inert supports, was dried in an oven. The driedbilayer was removed from the inert supports, cut into unit-dose films ofa predetermined size (22 mm×22 mm), and packaged into individual foilpouches. The resulting dried bilayer film was opaque white in color.

Film J

Film J is a bilayer film formed from an apomorphine layer containingcomponents and amounts listed in Table J1 and a neutralizing layercontaining the components and amounts listed in Table J2.

The apomorphine layer J1 was prepared by adding hydroxyethyl celluloseand hypromellose to water slowly while stirring until a uniform, clear,viscous liquid is produced. Sodium metabisulfite, disodium EDTAdihydrate, glycerin, maltodextrin, and sucralose were then added, andthe mixture was stirred. Acetone, glyceryl monostearate and menthol werethen added to the solution, and the mixture was stirred. Apomorphinehydrochloride was then added, with stirring, forming an opaquedispersion. The resulting mixture was placed under vacuum to eliminateair bubbles. The viscous liquid was then cast as a uniform layer onto aninert support and dried in an oven. The resulting dried layer was opaquewhite in color.

TABLE J1 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 36.9736 — — acetone 14.2616 — — sodium metabisulfite 0.4551 0.93320.4179 disodium EDTA, 0.4714 0.9667 0.4329 dihydrate apomorphine HCl16.3345 33.4966 15.0000 menthol 2.4973 5.1211 2.2933 glycerylmonostearate 0.4770 0.9781 0.4380 glycerin 4.4518 9.1292 4.0881maltodextrin M180 18.6597 38.2647 17.1352 sucralose 0.8512 1.7454 0.7816Natrosol 250 L 4.1082 8.4245 3.7725 Methocel E5 0.4587 0.9405 0.4212Total mass, mg 100.0000 100.0000 44.7807 Theoretical solids 48.7% — —

TABLE J2 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 60.68455 — — acetone 6.2112569 — — meglumine 19.594899 59.19169.9146 sodium metabisulfite 0.1395251 0.4215 0.0706 disodium EDTA,0.1164038 0.3516 0.0589 dihydrate glycerin 1.6141056 4.8758 0.8167maltodextrin M180 4.8965322 14.7913 2.4775 Natrosol 250 L 6.742727820.3682 3.4117 Total mass, mg 100.0000 100.0000 16.7500 Theoreticalsolids, % 33.1042 — —

Neutralizing layer J2 was prepared by adding hydroxyethyl cellulose towater slowly with stirring until a uniform, clear, viscous liquid wasproduced. Meglumine, sodium metabisulfite, disodium EDTA dihydrate,glycerin, and maltodextrin were then added, and the mixture was stirred.Acetone was added to this solution, and the mixture was stirred, until auniform, clear, viscous liquid was produced. The resulting mixture wasplaced under vacuum to eliminate air bubbles. The viscous liquid wasthen cast as a uniform layer onto an inert support and dried in an oven.The resulting dried layer was clear in appearance.

The separate Apomorphine hydrochloride layer and neutralizing layer werelaminated together by applying a spray of ethanol between them. Thisbilayer construction, sandwiched between two inert supports, was driedin an oven. The dried bilayer was removed from the inert supports, cutinto unit-dose films of a predetermined size (22 mm×22 mm), andsubsequently packaged into individual foil pouches. The resulting driedbilayer film was opaque white in color.

Film K

Film K is a bilayer film formed from an apomorphine layer containingcomponents and amounts listed in Table K1 and a neutralizing layercontaining the components and amounts listed in Table K2.

The apomorphine layer K1 was prepared by adding hydroxyethyl celluloseand hypromellose to water slowly while stirring until a uniform, clear,viscous liquid is produced. Sodium metabisulfite, disodium EDTAdihydrate, glycerin, maltodextrin, and sucralose were then added, andthe mixture was stirred. Acetone, glyceryl monostearate and menthol werethen added to the solution, and the mixture was stirred. Apomorphinehydrochloride was then added, with stirring, forming an opaquedispersion. The resulting mixture was placed under vacuum to eliminateair bubbles. The viscous liquid was then cast as a uniform layer onto aninert support and dried in an oven. The resulting dried layer was opaquewhite in color.

TABLE K1 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 36.9736 — — acetone 14.2616 — — sodium metabisulfite 0.4551 0.93320.4179 disodium EDTA, 0.4714 0.9667 0.4329 dihydrate apomorphine HCl16.3345 33.4966 15.0000 menthol 2.4973 5.1211 2.2933 glycerylmonostearate 0.4770 0.9781 0.4380 glycerin 4.4518 9.1292 4.0881maltodextrin M180 18.6597 38.2647 17.1352 sucralose 0.8512 1.7454 0.7816Natrosol 250 L 4.1082 8.4245 3.7725 Methocel E5 0.4587 0.9405 0.4212Total mass, mg 100.0000 100.0000 44.7807 Theoretical solids 48.7% — —

TABLE K2 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 60.7040 — — acetone 6.2195 — — pyridoxine HCl 19.6039 59.26849.9275 sodium hydroxide 3.3010 9.9800 1.6716 sodium metabisulfite 0.13560.4100 0.0687 disodium EDTA, 0.1205 0.3642 0.0610 dihydrate glycerin1.6617 5.0238 0.8415 maltodextrin M180 1.5089 4.5619 0.7641 Natrosol 250L 6.7449 20.3918 3.4156 Total mass, mg 100.0000 100.0000 16.7500Theoretical solids, % 33.0765 — —

Neutralizing layer K2 was prepared by adding hydroxyethyl cellulose towater slowly with stirring until a uniform, clear, viscous liquid wasproduced. Sodium hydroxide, pyridoxine HCl, sodium metabisulfite,disodium EDTA dihydrate, glycerin, and maltodextrin were then added, andthe mixture was stirred. Acetone was added to this solution, and themixture was stirred, until a uniform, clear, viscous liquid wasproduced. The resulting mixture was placed under vacuum to eliminate airbubbles. The viscous liquid was then cast as a uniform layer onto aninert support and dried in an oven. The resulting dried layer was clearin appearance.

The separate Apomorphine hydrochloride layer and neutralizing layer werelaminated together by applying a spray of ethanol between them. Thisbilayer construction, sandwiched between two inert supports, was driedin an oven. The dried bilayer was removed from the inert supports, cutinto unit-dose films of a predetermined size (22 mm×22 mm), andsubsequently packaged into individual foil pouches. The resulting driedbilayer film was opaque white in color.

Film L

Film L is a bilayer film formed from an apomorphine layer containingcomponents and amounts listed in Table L1 and a neutralizing layercontaining the components and amounts listed in Table L2.

The apomorphine layer L1 was prepared by adding hydroxyethyl celluloseand hypromellose to water slowly while stirring until a uniform, clear,viscous liquid is produced. Sodium metabisulfite, disodium EDTAdihydrate, glycerin, maltodextrin, and sucralose were then added, andthe mixture was stirred. Acetone, glyceryl monostearate and menthol werethen added to the solution, and the mixture was stirred. Apomorphinehydrochloride was then added, with stirring, forming an opaquedispersion. The resulting mixture was placed under vacuum to eliminateair bubbles. The viscous liquid was then cast as a uniform layer onto aninert support and dried in an oven. The resulting dried layer was opaquewhite in color.

TABLE L1 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 36.9736 — — acetone 14.2616 — — sodium metabisulfite 0.4551 0.93320.4179 disodium EDTA, 0.4714 0.9667 0.4329 dihydrate apomorphine HCl16.3345 33.4966 15.0000 menthol 2.4973 5.1211 2.2933 glycerylmonostearate 0.4770 0.9781 0.4380 glycerin 4.4518 9.1292 4.0881maltodextrin M180 18.6597 38.2647 17.1352 sucralose 0.8512 1.7454 0.7816Natrosol 250 L 4.1082 8.4245 3.7725 Methocel E5 0.4587 0.9405 0.4212Total mass, mg 100.0000 100.0000 44.7807 Theoretical solids 48.7% — —

TABLE L2 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 60.6845 — — acetone 6.2113 — — magnesium hydroxide 2.5949 7.83861.6000 sodium metabisulfite 0.1395 0.4215 0.0860 disodium EDTA,dihydrate 0.1164 0.3516 0.0718 glycerin 2.6141 7.8966 1.6118maltodextrin M180 13.8965 41.9782 8.5685 Natrosol 250 L PHARM 13.742741.5136 8.4737 Total mass, mg 100.0000 100.0000 20.4119 Theoreticalsolids, % 33.1042 — —

Neutralizing layer L2 was prepared by adding hydroxyethyl cellulose towater slowly with stirring until a uniform, clear, viscous liquid wasproduced. Sodium metabisulfite, disodium EDTA dihydrate, glycerin,maltodextrin, and magnesium hydroxide were all added, and the mixturewas stirred. Acetone was added to this solution, and the mixture wasstirred, until a uniform, opaque, viscous dispersion was produced. Theresulting mixture was placed under vacuum to eliminate air bubbles. Theviscous liquid was then cast as a uniform layer onto an inert supportand dried in an oven. The resulting dried layer was translucent white inappearance.

The separate Apomorphine hydrochloride layer and pH regulating layerwere laminated together by applying a spray of ethanol between them.This bilayer construction, sandwiched between two inert supports, wasdried in an oven. The dried bilayer was removed from the inert supports,cut into unit-dose films of a predetermined size (22 mm×22 mm), andsubsequently packaged into individual foil pouches. The resulting driedbilayer film was opaque white in color.

Example 2 Pharmacokinetics

Food was withheld from the animals for a minimum of 12 hours prior tostudy initiation and four hours post dose. Prior to dosing, animals wereweighed and assigned to experimental groups, stratified according tobody weight. Animals manifesting poor or irregular appetite prior tostudy were excluded. For sublingual administration of the test article,animals were placed in induction chamber and anesthetized withisoflurane using a face mask. The test article was placed under thetongue and the animal's mouth was closed, while it was also maintainedunder anesthesia. Five minutes post administration, the animal wasreleased. Blood samples were collected predosing, and at 10 minutes, 20minutes, 30 minutes, 1 hour, 2 hours, and 4 hours post test articleadministration via a percutaneous catheter in the auricular artery.Blood samples were stabilized and kept cold until analysis. Bioassayswere performed using C18RP-HPLC-MS. PK parameters for variousformulations were calculated using a non-compartmental (trapezoid) modeland are provided in Table 1 and Table 2 below.

TABLE 1 PK of films A, B, C, D, and E. PK values sc inj^(a) A B C D EDose administered 0.5 0.28 0.28 0.28 0.28 0.28 (mg/kg) N = 6 5 5 5 5 5C_(max) (ng/mL) 331 116 117 39 104 166 T_(max) (minutes) 25 20 32 10 3532 AUC_(inf) 17828 10142 8150 1107 8707 11967 (ng/mL · minute)Bioavailability (%)^(b) 100 96 77 10 87 109 ^(a)Literature value.^(b)Relative to 100% bioavailability for administration by subcutaneousinjection.

TABLE 2 PK of films F, G, H, J, and K. PK values sc inj^(a) F G H J KDose administered 0.5 0.28 0.28 0.28 0.28 0.28 (mg/kg) N =^(b) 6 4 5 5 88 C_(max) (ng/mL) 331 94 132 91 107 100 T_(max) (minutes) 25 25 40 28 1314 AUC_(inf) 17828 6210 9511 6285 5019 5680 (ng/mL · minute)Bioavailability (%)^(c) 100 61 82 66 57 65 ^(a)Literature value.^(b)Number of rabbits tested (for Film F, 5 rabbits were dosed, but onedata point was rejected as an outlier (>2 SD from mean). ^(c)Relative to100% bioavailability for administration by subcutaneous injection.

Film A (the only film that includes propylene glycol) incorporates theapomorphine hydrochloride dissolved in the monolayer at highconcentration, and exhibits rapid dissolution, and rapid initial uptake.Preliminary stability suggests lower stability than that observed forFilm B (a glycerol monolayer formulation that includes crystallineapomorphine hydrochloride).

Film C combines the apomorphine layer of Film B with a pH neutralizinglayer containing carboxymethyl cellulose and inorganic phosphate as abase. Five minutes after dosing in the rabbit with Film C, a largeportion of the film was recovered. Analysis showed it to be theapomorphine layer undissolved. We determined that the apomorphine layerdoes not dissolve well in phosphate buffer, which explains the low AUCand C_(max) observed for this formulation. The rapid T_(max) observedfor Film C appears to be an artifact of the poor dissolution of theapomorphine layer.

Films D and E were designed to dissolve more rapidly by including alarge portion of hydrolyzed starch as a disintegrant. In the case ofFilm E, the phosphate was replaced with an organic base (meglumine) tominimize interference with the dissolution of the apomorphine layer.Film D exhibited slower uptake and higher variability (rabbit to rabbit)than Films A or B. Film E was superior to Film D, but exhibited sloweruptake than Films A and B.

In Films F, G, and H, the amount of apomorphine hydrochloride in theapomorphine layer was increased to 55% (w/w). Films F, G, and H utilizean organic base (i.e., meglumine for Film F; citrate for Film G, and amixture of meglumine and citrate for Film H).

Film F exhibited a lower AUC and C_(max), slightly shorter T_(max), andless variability.

In contrast, Film G exhibited high AUC and C_(max) values, but a longerT_(max) and higher variability than Film F.

Film H performed similarly to Film F.

To assess the impact of water on the pharmacokinetic parameters, weadded 200 μl water to the rabbit's mouth after dosing with Film H. Weobserved that AUC and C_(max) increased, but T_(max) increased as well.Water did not help to accelerate absorption at early time points.

Mineral (inorganic) pH neutralizers seem to lead to lower C_(max),higher T_(max) and higher variability. Citrate seems to be bettertolerated than phosphate. Meglumine appears to give best results.

Films E, F, H, J, and K exhibit pharmacokinetic parameters closest to asubcutaneous injection (best peak shape) after dose adjustment (i.e.,using larger quantities of apomorphine hydrochloride), with Films J andK demonstrating the fastest T_(max) values and PK values closest tothose observed for subcutaneous injection of apomorphine hydrochloride.

All the bilayers have about the same initial rate of absorption (i.e.,40 ng/ml in blood at 10 minutes post dosing).

We have observed that the monolayers have the fastest initial onset ofabsorption. This is surprising given the fact that the drug isprotonated (see Example 6). Since the neutral apomorphine has a muchhigher rate of permeability than the protonated form, we can concludethat absorption of the monolayer is accompanied by release of thehydrochloride salt from the apomorphine and into the tissue. Since HClis potential irritant when left unbuffered (saliva is unbuffered),increasing pH may avoid any tissue irritation and so the use of a pHneutralizer (i.e., to a pH of 2.5 to 5.5) may be desired.

All dosing has been with the sublingual film placed against the bottomof the mouth (not on the underside of tongue) and with apomorphine layerin direct contact with the tissues.

Example 3 Dispersed Milled Apomorphine in Bilayer Film

Using methods analogous to those described in Example 1, a jet-milledpowder of apomorphine hydrochloride (D95<20 μm) is added, along with theother components of the apomorphine layer, to a mixture of ethanol andethylacetate to create a homogeneous dispersion. The mixture is spreadon a thin plastic liner and dried to produce a film. This film can beadministered as is or combined with a neutralizing layer as perExample 1. Also contemplated, is the addition of jet-milled pHneutralizing agent to the neutralizing layer either for inclusion withthe apomorphine (i.e., to produce a single layer wherein both activeapomorphine hydrochloride and a neutralizing agent are dispersed assolid agents within a single layer), or to a neutralizing layer (i.e.,to form a bilayer film).

Example 4 Dosage Forms Including Permeation Enhancers

Using methods analogous to those described in Example 1, from 0.2 to 2%(w/w) permeation enhancer is included in the apomorphine layer of any offilms A-H, or, optionally, in both layers of the bilayer film. Thepermeation enhancer can be glycerol monostearate, or any permeationenhancer described herein.

Example 5 Permeability Studies

Freshly collected buccal tissues were obtained from pig and mucosa'swere isolated carefully. The prepared mucosa membranes with approximatesize of 4 cm² were mounted between donor and receiver chambers of Franzdiffusion cells with available diffusion area of 1.77 cm². Testtreatments and controls were run in quadruplicate. The receivercompartment, which contained a stirring bar, was filled with 8 mL of KRBbuffer, pH 7.4 containing 1% BSA. The Franz cells were placed in aheating/stirring block. The temperature was set at 37° C. in order tomaintain the tissue surface temperature at 32° C.; the stirring rate wasset at 400 rpm. Two milliliters of formulated compound at different pHswas added to the donor chambers, completely covering the exposed mucosa.All dosing solutions contained 0.1% of sodium dithionite, 0.2% DMSO and5% propylene glycol or glycerin. The donor compartment was covered withParafilm to minimize evaporation. An aliquot (˜0.5 mL) was taken fromthe receiver compartment at 2, 60, 90, and 120 min and replaced with anequal volume of buffer warmed at 37° C. Sampling time points from donorcompartment were 0, 60, 90 and 120 min. Samples were diluted with 0.5 mL(1:1) of 10% aq. ascorbic acid. The concentration of each analyte wasquantified by LC-MS/MS (Appendix I). The whole study was done in darkwith yellow light, and glass vials and syringes were used for sampling.The apparent permeability coefficient (Papp), total amount of flux andpercent recovery of control and test compounds were calculated asfollows:Papp=(dCr/dt)·Vr/(A·C0)Normalized Papp=(dCr/dt)·Vr/(A·(Cd initial+Cd final)/2)Flux=(dCr/dt)·Vr/(A)Percent Recovery=100·((Vr·Cr final)+(Vd·Cd final))/(Vd·C0)In the above equations, dC_(r)/dt is the slope of the cumulativereceiver compartment concentration versus time, μM·min-1; A is thediffusional surface area of the exposed skin membrane, 1.77 cm²; V_(r)is the volume of the receiver compartment, 8.0 mL; V_(d) is the volumeof the donor compartment, 2.0 mL; C_(r) is the cumulative receivercompartment concentration in μM; C₀ is the concentration of the donor at0 minutes of the incubation, μM; C_(r final) is the concentration of thereceiver at the end of the incubation period, μM; C_(d initial) is theconcentration of the donor at the beginning of the incubation period(interval), μM. C_(d final) is the concentration of the donor at the endof the incubation period (interval), μM. The results are tabulatedbelow.

Treatement tested Papp pH 6.4 0.071 pH 6.8 0.054 pH 7.4 0.185 pH 8.00.556 pH 8.0 + 1% glycerin monostearate 2.34 pH 8.0 + 1% magnesiumstearate 0.3 pH 8.0 + 1% tocopherol acetate 0.98

Glycerin monostearate and tocopherol acetate increase the apparent rateof permeability through excised buccal tissue, while magnesium stearateretards permeation.

Example 6 Ropinerol Bilayer Film

A bilayer film is formed from an ropinerol containing the components andamounts listed in Table R1 and a neutralizing layer containing thecomponents and amounts listed in Table R2.

The API Layer R1 is prepared by slowly adding hydroxyethyl cellulose andhypromellose to water with stirring until a uniform, clear, viscousliquid is produced. Disodium EDTA, glycerin, maltodextrin, and sucraloseare then all added, and the mixture is stirred. Acetone and menthol areadded to this solution, and the mixture is stirred. Ropinerolhydrochloride is then added with stirring, forming an opaque dispersion.The resulting mixture is placed under vacuum to eliminate air bubbles,cast as a uniform layer onto an inert support, and dried in an oven.

TABLE R1 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgWater 38.6792 — — Acetone 14.1509 — — disodium EDTA 0.4643 0.9843 0.4249ropinerol HCl 16.3912 34.7494 15.0000 menthol 2.5050 5.3105 2.2924glycerin 4.3386 9.1978 3.9703 Maltrin M180 19.2072 40.7194 17.5770sucralose 0.8698 1.8439 0.7959 Natrosol 250 G 1.2332 2.6145 1.1286Natrosol 250 L 1.2332 2.6145 1.1286 Methocel E5 0.4584 0.9718 0.4195Total mass, mg 100.0000 100.0000 43.1662 Theoretical solids, % 47.1698 ——

Neutralizing layer R2 is prepared by slowly adding hydroxyethylcellulose to water with stirring until a uniform, clear, viscous liquidis produced. Pyridoxine, disodium EDTA, glycerin, and maltodextrin arethen all added, and the mixture is stirred. Acetone is added to thissolution, and the mixture stirred, until a uniform, clear, viscousliquid was produced. The resulting mixture is placed under vacuum toeliminate air bubbles, cast as a uniform layer onto an inert support,and dried in an oven.

TABLE R2 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 85.8172 — — acetone 1.7129 — — pyridoxine 5.1388 41.2092 10.3023sodium metabisulfite 0.0370 0.2965 0.0741 disodium EDTA 0.0314 0.25200.0630 glycerin 1.0963 8.7913 2.1978 Maltrin M180 0.6852 5.4946 1.3736Natrosol 250 G 2.7407 21.9782 5.4946 Natrosol 250 L 2.7407 21.97825.4946 Total mass, mg 100.0000 100.0000 25.0000 Theoretical solids, %12.4699 — —

The dopamine agonist (ropinerol) layer and neutralizing layer werelaminated together by applying a spray of ethanol between them. Thisbilayer construction, sandwiched between two inert supports, was driedin an oven. The dried bilayer was removed from the inert supports, cutinto unit-dose films of a predetermined size and packaged intoindividual foil pouches. The resulting dried bilayer film was opaquewhite in color.

Example 7 Irritation Testing (General Method)

On Day 1, Adult Golden Syrian hamsters (approx 8 weeks of age and 100grams), apportioned 36 control (18/sec) and 30 test article-treated(15/sex), are anaesthetized. Approximately 1 cm² of the left buccalpouch cheek is abraded by manually scraping with a scalpel to removesurface layer of tissue without bleeding. On Day 2, test articles areapplied to cheek pouches on both sides, abraded and non, at 9 am, 1 μmand 5 μm (t.i.d). Dosing is continued for a total of 28 days (ie, to Day29). Control animals are treated similarly but with a control filmapplied to both cheek pouches. The control film is formulated asdescribed above in the examples, but (i) without any dopamine agonist,(ii) without a pH neutralizing agent, and (iii) with sufficient acid(e.g., succinic acid, acetic acid, or an inorganic acid) to produce a pHof less than 3 following administration to, and dissolution in, thecheek pouch of an animal. Systemic signs, body weight and foodconsumption are recorded daily. Cheeks everted, cleared of food bywashing with distilled water and gauze, and examined for signs ofirritation prior to the first dose on Days 1, 2, 3, 4, 8, 14, & 21 andprior to necropsy on Day 29. Necropies are recorded on Day 2: 3controls/sex; Day 5: 5 control & 5 treated animals/sex; Day 29: 5controls & 5 treated animals/sex; Day 43: 5 controls & 5 treatedanimals/sex with examination of gross signs and histopathology of cheekpouches. Each animal can be monitored for both the extent of irritationfollowing an administration. For abraded animals, the animals can bemonitored for the amount of time required to observe healing in thecheek while receiving treatment.

The compositions of the invention can be non-irritating (e.g.,performing equal to, or better than, a placebo formulation free of anacid addition salt of the active) as determined using the test describedabove.

Example 8 Stability of Packaged Films Including ApomorphineHydrochloride

Films (see Example 1) were packaged individually in plastic-linedaluminum foils and thermally sealed to eliminate all contact with air orlight. The films were tested for stability by placing the packaged filmsin an over at 40° C. After 2 months the color of the films was observedfor any color change that would indicate oxidation of apomorphine to aquinone-type product, which are blue to green (see Rehse Achives desPharmazie 1969, 7, 488). The results are provided in Table 3.

TABLE 3 Film 1 months at 40° C. 2 months at 40° C. A Uncolored to lightbeige Blue B Uncolored to light beige Uncolored to light beige CUncolored to light beige Uncolored to light beige D Not tested Euncolored Light blue F Not tested G uncolored Light blue H Not tested Juncolored Light blue K uncolored uncolored

Example 9 Tissue Histology Studies

Animals (8 per group) were dosed 3 times with either bilayer Film J orFilm K (7 mm disk, 1.1 mg apomorphine hydrochloride prepared accordingto Example 1) with an interval of 2 hours between dosing. With each doseadministered, 500 μl of water was added to the sublingual regionimmediately after administering the dose to mimic salivation.Approximately 4 hours after the last dose, animals were euthanized, thetongue and the adjacent sublingual tissue were harvested and immediatelyfixed by placing in 10% formalin. Tissues were processes and embedded inparaffin, sectioned and stained with hematoxylin and eosin (H&E). Threesections of the tongue and sublingual tissues were trimmed andprocessed. Histological slides were made from the tissue to slide fromeach animal to include right, midline and left sections to ensure thatthe dose application site was examined microscopically. Resulting slideswere examined.

There were no macroscopic observations (i.e., there was no evidence ofirritation) due to the test article. In all slides, there were nomicroscopic findings in either group relating to the application ofbilayer test strips. There is no evidence of local irritation related tomultidose application of the strip according to the procedure.

Example 10 Bilayer Films Prepared for Clinical Studies

Placebo (film M) and API (film N) bilayer films were prepared asdescribed below for use in clinical studies.

Placebo Film (M1)

The placebo film is a bilayer film formed without apomorphine andcontains components and amounts listed in Table M1 and a neutralizinglayer containing the components and amounts listed in Table M2.

The apomorphine layer M1 was prepared by combining acetone, glycerylmonostearate, and menthol with stirring until a uniform, clear solutionwas produced. Water was added, and the mixture was stirred. Hypromellosewas then added to this solution slowly with stirring until a uniform,clear liquid was produced. Sodium metabisulfite and disodium EDTAdihydrate were then added, with stirring until a uniform liquid wasproduced. Hydroxyethyl cellulose was added to this solution slowly withstirring until a uniform, clear, viscous liquid was produced. Glycerin,maltodextrin, and sucralose were then added with stirring until auniform, clear, viscous liquid was produced. The resulting mixture wasplaced under vacuum to eliminate air bubbles. The viscous liquid wasthen cast as a uniform layer onto an inert support and dried in an oven.The resulting dried layer was clear/hazy in appearance.

TABLE M1 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 60.9548 — — acetone 11.0307 — — sodium metabisulfite 0.5522 1.97100.4820 disodium EDTA, 0.5555 1.9830 0.4849 dihydrate menthol 2.30728.2357 2.0140 glycerin 1.8994 6.7800 1.6580 glyceryl monostearate 0.33431.1933 0.2918 maltodextrin M180 9.9469 35.5063 8.6829 sucralose 1.41895.0647 1.2385 Natrosol 250 L 10.5069 37.5053 9.1717 Methocel E5 0.49321.7606 0.4305 Total mass, mg 100.0000 100.0000 24.4544 Theoreticalsolids, % 28.0145 — —

TABLE M2 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 59.1217 — — acetone 10.7182 — — pyridoxine HCl 2.4449 8.10651.6300 sodium hydroxide 0.4886 1.6201 0.3258 sodium metabisulfite 0.55711.8471 0.3714 disodium EDTA, 0.5589 1.8531 0.3726 dihydrate menthol2.3341 7.7390 1.5561 glycerin 1.6712 5.5412 1.1142 glyceryl monostearate0.3180 1.0544 0.2120 maltodextrin M180 10.0977 33.4803 6.7320 sucralose1.3778 4.5684 0.9186 Natrosol 250 L 10.3118 34.1900 6.8747 Total mass,mg 100.0000 100.0000 20.1074 Theoretical solids, % 30.1601 — —

Neutralizing layer M2 was prepared by combining acetone, glycerylmonostearate, and menthol to form a mixture. The mixture was stirreduntil a uniform, clear solution was produced. Water was added, and themixture was stirred. Sodium hydroxide, pyridoxine HCl, sodiummetabisulfite, and disodium EDTA dihydrate were then added with stirringuntil a uniform, clear liquid was produced. Hydroxyethyl cellulose wasadded to this solution slowly with stirring until a uniform, clear,viscous liquid was produced. Glycerin, maltodextrin, and sucralose werethen added with stirring until a uniform, clear, viscous liquid wasproduced. The resulting mixture was placed under vacuum to eliminate airbubbles. The resulting viscous liquid was cast as a uniform layer onto aseparate placebo dried layer (film M1) against an inert support, anddried in an oven. The resulting dried bilayer was removed from the inertsupport, cut into unit-dose films of a predetermined size (22 mm×22 mm),and subsequently packaged into individual foil pouches. The resultingdried bilayer film was clear/hazy in appearance.

Film N (API Bilayer Film for Trial Studies)

Film N is a bilayer film formed from an apomorphine layer containingcomponents and amounts listed in Table N1 and a neutralizing layercontaining the components and amounts listed in Table N2.

The apomorphine layer N1 was prepared by combining acetone, glycerylmonostearate, and menthol with stirring until a uniform, clear solutionwas produced. Apomorphine hydrochloride (milled to an effective particlesize of about 8 μm using a Jet-Pulverizer 2 Micron-Master cyclonedischarge mill with stainless steel liner as described in Example 1) wasadded with stirring, forming an opaque dispersion. Water was added, andthe mixture was stirred. Hypromellose was added to this solution slowlywith stirring until a uniform, clear liquid was produced. Sodiummetabisulfite and disodium EDTA dihydrate were then added with stirringuntil a uniform liquid was produced. Hydroxyethyl cellulose was added tothis solution slowly with stirring until a uniform, clear, viscousliquid was produced. Glycerin, maltodextrin, and sucralose were thenadded with stirring until a uniform, clear, viscous liquid was produced.The resulting mixture was placed under vacuum to eliminate air bubbles.The viscous liquid was then cast as a uniform layer onto an inertsupport and dried in an oven. The resulting dried layer was clear/hazyin appearance.

TABLE N1 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 58.6167 — — acetone 10.6170 — — sodium metabisulfite 0.5322 1.72970.4230 disodium EDTA, 0.5325 1.7309 0.4233 dihydrate apomorphine HCl3.7743 12.2677 3.0000 menthol 2.2274 7.2397 1.7704 glycerin 1.84896.0096 1.4696 glyceryl monostearate 0.3171 1.0306 0.2520 maltodextrinM180 9.5753 31.1228 7.6109 sucralose 1.3674 4.4444 1.0869 Natrosol 250 L10.1139 32.8735 8.0390 Methocel E5 0.4772 1.5511 0.3793 Total mass, mg100.0000 100.0000 24.4544 Theoretical solids, % 30.7662 — —

TABLE N2 bulk liquid dry film dry film Component mg/100 mg mg/100 mg mgwater 59.1217 — — acetone 10.7182 — — pyridoxine HCl 2.4449 8.10651.6300 sodium hydroxide 0.4886 1.6201 0.3258 sodium metabisulfite 0.55711.8471 0.3714 disodium EDTA, 0.5589 1.8531 0.3726 dihydrate menthol2.3341 7.7390 1.5561 glycerin 1.6712 5.5412 1.1142 glyceryl monostearate0.3180 1.0544 0.2120 maltodextrin M180 10.0977 33.4803 6.7320 sucralose1.3778 4.5684 0.9186 Natrosol 250 L 10.3118 34.1900 6.8747 Total mass,mg 100.0000 100.0000 20.1074 Theoretical solids, % 30.1601 — —

Neutralizing layer N2 was prepared by combining acetone, glycerylmonostearate, and menthol to form a mixture. The mixture was stirreduntil a uniform, clear solution was produced. Water was added, and themixture was stirred. Sodium hydroxide, pyridoxine HCl, sodiummetabisulfite, and disodium EDTA dihydrate were then added with stirringuntil a uniform, clear liquid was produced. Hydroxyethyl cellulose wasadded to this solution slowly with stirring until a uniform, clear,viscous liquid was produced. Glycerin, maltodextrin, and sucralose werethen added with stirring until a uniform, clear, viscous liquid wasproduced. The resulting mixture was placed under vacuum to eliminate airbubbles. The resulting viscous liquid was cast as a uniform layer onto aseparate Apomorphine HCl containing dried layer (film N1) against aninert support, and dried in an oven. The resulting dried bilayer wasremoved from the inert support, cut into unit-dose films of apredetermined size (22 mm×22 mm), and subsequently packaged intoindividual foil pouches. The resulting dried bilayer film was clear/hazyin appearance.

When a 3 mg, 22 mm×22 mm unit is placed in 10 mL of pure milliQ waterwith a stir bar, a pH of between 4.5 and 6.5 is measured.

Example 11 Phase I Trial

A single center phase I trial in 15 healthy subjects was designed toassess the single dose pharmacokinetics, safety and tolerability of asingle dose of film N administered in a crossover design. 15 healthymale volunteers are pre-treated with an anti-emetic (10 mg domperidone)for three days. The first day, 12 subjects receive a dose equivalent to3 mg apomorphine hydrochloride formulated as film N with the drug layerfacing down, toward the floor of the mouth. 3 subjects receive theplacebo film M. Blood samples (5 ml) are drawn from all subjects priorto dosing, and at 10, 20, 30, 45, 60, 90, 120, 180, 240 minutespost-dose. The blood is immediately centrifuged to recover the plasmawhich is then stored on dry ice. After a 24 hour washout period, thesame subjects are dosed a second time with the same test product andplaced in the floor of the mouth but with the drug layer oriented uptoward the underside of the tongue.

Assessments include PK determination and local tolerance.

Other Embodiments

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each independent publication or patent application was specificallyand individually indicated to be incorporated by reference.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure that come within known or customary practice withinthe art to which the invention pertains and may be applied to theessential features hereinbefore set forth, and follows in the scope ofthe claims.

This application claims benefit of and priority to U.S. ProvisionalApplication No. 61/423,858, filed Dec. 16, 2010, and U.S. ProvisionalApplication No. 61/483,864, filed May 9, 2011, each of which isincorporated by reference herein in its entirety.

Other embodiments are within the claims.

What is claimed is:
 1. A pharmaceutical composition in unit dosage formformulated for sublingual administration, wherein said unit dosage formis a film comprising a first portion comprising apomorphinehydrochloride and a second portion comprising from 10±2 to 50±5% (w/w)of a pH neutralizing agent that is an organic base having a pKa of 5±2,wherein said unit dosage form comprises from 2 to 60 mg of apomorphinehydrochloride.
 2. The pharmaceutical composition of claim 1, whereinsaid unit dosage form further comprises a high molecular weight polymerhaving a weight average molecular weight of greater than 60 KDa selectedfrom hydroxypropyl cellulose, hydroxypropyl methyl cellulose,hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose.3. The pharmaceutical composition of claim 1, wherein said unit dosageform further comprises a low molecular weight polymer having a weightaverage molecular weight of from 5 KDa to 50 KDa selected fromhydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethylcellulose, carboxymethyl cellulose, and methyl cellulose.
 4. Thepharmaceutical composition of claim 1, wherein said pH neutralizingagent is pyridoxine.
 5. The pharmaceutical composition of claim 1,further comprising 1±0.5% (w/w) permeation enhancer.
 6. Thepharmaceutical composition of claim 5, wherein said permeation enhanceris glycerol monosterate.
 7. The pharmaceutical composition of claim 1,wherein said pharmaceutical composition comprises from 3 to 15% (w/w)plasticizing agent.
 8. The pharmaceutical composition of claim 1,wherein said plasticizing agent is a polyol, oleic acid, or triacetin.9. The pharmaceutical composition of claim 8, wherein said plasticizingagent is a polyol selected from sorbitol, mannitol, maltitol, xylitol,glycerol, propylene glycol, and polyethylene glycol.
 10. Thepharmaceutical composition of any claim 1, wherein said pharmaceuticalcomposition further comprises from 1 to 50% (w/w) hydrolyzed starch. 11.The pharmaceutical composition of claim 10, wherein said hydrolyzedstarch is a dextrin.
 12. The pharmaceutical composition of claim 11,wherein said hydrolyzed starch is a maltodextrin.
 13. The pharmaceuticalcomposition of claim 1, wherein said pharmaceutical composition furthercomprises an antioxidant.
 14. The pharmaceutical composition of claim13, wherein said pharmaceutical composition further comprises from 0.05to 2.5% (w/w) metabisulfite.
 15. The pharmaceutical composition of claim1, wherein said pharmaceutical composition has a sublingualbioavailability of greater than 40%.
 16. The pharmaceutical compositionof claim 1, wherein said pharmaceutical composition has a T_(max) offrom 10 to 25 minutes.
 17. The pharmaceutical composition of claim 1,wherein following sublingual administration to a subject said unitdosage form produces an average circulating apomorphine concentration ofat least 3 ng/mL within a period of from 5 to 15 minutes.
 18. Thepharmaceutical composition of claim 1, wherein said unit dosage formwhen administered sublingually to a subject is non-irritating.
 19. Thepharmaceutical composition of claim 1, wherein said unit dosage form isan individual film packaged in a sealed plastic-lined aluminum foil,wherein said unit dosage form is stable for a period of at least 2months at 40° C.
 20. The pharmaceutical composition of claim 1, whereinsaid film comprises a solid solution of apomorphine hydrochloride. 21.The pharmaceutical composition of claim 1, wherein said film comprisesparticles of apomorphine hydrochloride.
 22. The pharmaceuticalcomposition of claim 21, wherein said particles have an effectiveparticle size of from 20 nm to 10 μm.
 23. The pharmaceutical compositionof claim 1, wherein said unit dosage form when placed in 1 mL ofunbuffered water at pH 7 results in a solution having a pH of between2.5 and 8.0.
 24. A method of treating Parkinson's disease in a subject,said method comprising sublingual administration of a pharmaceuticalcomposition of claim 1 in an amount effective to treat said subject. 25.The pharmaceutical composition of claim 1, wherein said unit dosage formcomprises 12±3 mg of apomorphine hydrochloride.
 26. The pharmaceuticalcomposition of claim 1, wherein said unit dosage form comprises 22±4 mgof apomorphine hydrochloride.
 27. The pharmaceutical composition ofclaim 1, wherein said unit dosage form comprises 30±5 mg of apomorphinehydrochloride.
 28. The pharmaceutical composition of claim 1, whereineach said portion is a layer.
 29. A method of treating restless legsyndrome in a subject, said method comprising sublingual administrationof a pharmaceutical composition of claim 1 in an amount effective totreat said subject.